Patent Publication Number: US-11028444-B2

Title: Survival predictor for diffuse large B cell lymphoma

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation application of U.S. patent application Ser. No. 14/540,302, filed Nov. 13, 2014, which is a continuation application of U.S. patent application Ser. No. 12/996,489, filed Dec. 6, 2010, which is a U.S. National Phase of International Patent Application No. PCT/US2009/046421, filed Jun. 5, 2009, which claims the benefit of U.S. Provisional Patent Application No. 61/059,678, filed on Jun. 6, 2008, the disclosures of each incorporated by reference. 
    
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT 
     This invention was made with Government support under Grant No. U01 CA084967, awarded by NIH. This invention was made with Government support under project number Z01 ZIA BC 011006 by the National Institutes of Health, National Cancer institute. The Government has certain rights in the invention. 
    
    
     INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY 
     Incorporated by reference in its entirety herein is a computer-readable nucleotide/amino acid sequence listing submitted concurrently herewith and identified as follows: One 1,232,314 Byte ASCII (Text) file named 738944_ST25.TXT created on Apr. 27, 2018. 
     BACKGROUND OF THE INVENTION 
     The current standard of care for the treatment of diffuse large B cell lymphoma (DLBCL) includes anthracycline-based chemotherapy regimens such as CHOP in combination with the administration of the anti-CD20 monoclonal antibody Rituximab. This combination regimen (R-CHOP) can cure about 60% of patients and has improved the overall survival of DLBCL patients by 10-15% (Coiffier et al.,  N. Engl. J. Med.,  346: 235-42 (2002)). Nonetheless, the molecular basis of response or resistance to this therapy is unknown. 
     DLBCL is a molecularly heterogeneous disease (Staudt et al.,  Adv. Immunol.,  87: 163-208 (2005)), and different molecular subtypes of DLBCL can have very different prognoses following treatment. For example, gene expression profiling has identified two molecular subtypes of DLBCL that are biologically and clinically distinct (Rosenwald et al.,  N. Engl. J. Med.,  346: 1937-47 (2002); Alizadeh et al.,  Nature,  403: 503-11 (2000)). The germinal center B cell-like (GCB) DLBCL subtype likely arises from normal germinal center B cells, whereas the activated B cell-like (ABC) DLBCL subtype may arise from a post-germinal center B cell that is blocked during plasmacytic differentiation. Many oncogenic mechanisms distinguish these subtypes: GCB DLBCLs have recurrent t(14,18) translocations, whereas ABC DLBCLs have recurrent trisomy 3 and deletion of the INK4a/ARF locus as well as constitutive activation of the anti-apoptotic NF-kB signalling pathway (Rosenwald et al.,  N. Engl. J. Med.,  346: 1937-47 (2002); Bea et al.,  Blood,  106: 3183-90 (2005); Tagawa et al.,  Blood,  106: 1770-77 (2005); Davis et al.,  J. Exp. Med.,  194:1861-74 (2001); Ngo et al.,  Nature,  441: 106-10 (2006); Lenz et al.,  Science,  319: 1676-79 (2008)). When treated with CHOP-like chemotherapy, the overall survival rates of patients with GCB DLBCL and ABC DLBCL were 60% and 30%, respectively (Wright et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  100: 9991-96 (2003)). Thus, the prognosis for different DLBCL can vary widely. 
     A separate analytical approach identified four gene expression signatures that reflect distinct DLBCL tumor attributes and that were associated with distinct survival profiles in CHOP-treated DLBCL patients (Rosenwald et al.,  N. Engl. J. Med.,  346: 1937-47 (2002)). A “germinal center B cell” (GCB) signature was associated with a favorable prognosis and paralleled the distinction between ABC and GCB DLBCL. The “proliferation” signature was associated with an adverse prognosis and included MYC and its target genes. The “MHC class II” signature was silenced in the malignant cells in a subset of DLBCL cases, an event that was associated with inferior survival (Rosenwald et al.,  N. Engl. J. Med.,  346: 1937-47 (2002); Rimsza et al.,  Blood,  103: 4251-58 (2004)). A fourth prognostic signature, termed “lymph node” signature was associated with favorable prognosis and included components of the extracellular matrix, suggesting that it reflects the nature of the tumor-infiltrating non-malignant cells. These signatures predicted survival in a statistically independent fashion, indicating that multiple biological variables dictate the response to CHOP chemotherapy in DLBCL. 
     Reports have suggested that the benefit of Rituximab immunotherapy might be restricted to certain molecular subtypes of DLBCL. High expression of BCL-2 or low expression of BCL-6 was associated with inferior survival with CHOP therapy. However, this distinction disappeared with R-CHOP therapy (Mounier et al.,  Blood,  101: 4279-84 (2003); Winter et al.,  Blood,  107: 4207-13 (2006)). Immunohistochemistry has also been used to distinguish DLBCLs with a germinal center versus post-germinal center phenotype. Although such immunohistochemical phenotypes were prognostically significant in CHOP-treated cases, they were not prognostic for R-CHOP-treated cases (Nyman et al.,  Blood,  109: 4930-35 (2007)). 
     Accordingly, there is a need for new methods of distinguishing among DLBCL subtypes that is prognostically significant for R-CHOP-treated patients. 
     BRIEF SUMMARY OF THE INVENTION 
     The invention provides methods and arrays related to a gene expression-based survival predictor for DLBCL patients, including patients treated with the current standard of care, which includes chemotherapy and the administration of Rituximab. 
     The invention provides a method of predicting the survival outcome of a subject suffering from diffuse large B cell lymphoma (DLBCL) that includes obtaining a gene expression profile from one or more DLBCL biopsy samples from the subject. The gene expression profile, which can be derived from gene expression product isolated from the one or more biopsy samples, includes an expression level for each gene in a germinal center B cell (GCB) gene expression signature and each gene in a stromal-1 gene expression signature. From the gene expression profile, a GCB signature value and a stromal-1 signature value are derived. From these values, a survival predictor score can be calculated using an equation that includes subtracting [(x)*(the GCB signature value)] and subtracting [(y)*(the stromal-1 signature value)]. In the equation, (x) and (y) are scale factors. A lower survival predictor score indicates a more favorable survival outcome, and a higher survival predictor score indicates a less favorable survival outcome for the subject. 
     The invention also provides a method of generating a survival estimate curve for subjects suffering from DLBCL. Generally the method includes obtaining a gene expression profile from one or more DLBCL biopsy samples taken from each member of a plurality of subjects. Each gene expression profile, which can be derived from gene expression product isolated from the one or more biopsy samples taken from each subject, includes an expression level for each gene in a GCB expression signature, a stromal-1 gene expression signature, and a stromal-2 gene expression signature. For each subject, the GCB signature value, the stromal-1 signature value, and the stromal-2 signature value are determined from the subject&#39;s gene expression profile, and, for each subject, a survival predictor score is generated. Each subject&#39;s survival outcome following treatment for DLBCL is tracked. A survival estimate curve is generated which correlates the probability of the tracked survival outcome with time following treatment for DLBCL and which also correlates the tracked outcome over time with the survival predictor score for the subjects. 
     The invention additionally provides a method of predicting the survival outcome of a subject suffering from DLBCL. Generally, the method includes obtaining a gene expression profile from one or more DLBCL biopsy samples from the subject. The gene expression profile, which can be derived from gene expression product isolated from the one or more biopsy samples, includes an expression level for each gene in a GCB gene expression signature, each gene in a stromal-1 gene expression signature, and each gene in a stromal-2 gene expression signature. The GCB signature value, the stromal-1 signature value, and the stromal-2 signature value are determined from the gene expression profile. The method then includes calculating a survival predictor score using the equation:
 
survival predictor score= A −[( x )*(the  GCB  signature value)]−[( y )*(the stromal-1 signature value)]+[( z )*(the stromal-2 signature value)].
 
In this equation, A is an offset term, and (x), (y), and (z) are scale factors. The method further includes calculating the probability of a survival outcome for the subject beyond an amount of time t following treatment for DLBCL, wherein the subject&#39;s probability of the survival outcome P(SO) is calculated using the equation:
 
 P ( SO )= SO   0 ( t ) (exp((s)*survival predictor score))  
 
In this equation, SO 0 (t) is the probability of the survival outcome, which corresponds to the largest time value smaller than tin a survival outcome curve, and wherein (s) is a scale factor.
 
     Furthermore, the invention provides a method of evaluating a subject for antiangiogenic therapy of DLBCL. The method includes obtaining a gene expression profile from one or more DLBCL biopsy samples from the subject. The gene expression profile, which can be derived from gene expression product isolated from the one or more biopsy samples, includes an expression level for each gene in a stromal-2 signature. The subject&#39;s stromal-2 signature value is then derived from the gene expression profile and evaluated to determine whether the subject&#39;s stromal-2 signature value is higher or lower than a standard stromal-2 value. If the subject&#39;s stromal-2 signature value is higher than the standard stromal-2 value, then antiangiogenic therapy is indicated, and the subject can be treated with antiangiogenic therapy. If the subject&#39;s stromal-2 signature value is not higher than the standard stromal-2 value, then antiangiogenic therapy is not indicated. 
     The invention also provides a second method of evaluating a subject for antiangiogenic therapy of DLBCL. The method includes obtaining a gene expression profile from one or more DLBCL biopsy samples from the subject. The gene expression profile, which can be derived from gene expression product isolated from the one or more biopsy samples, includes an expression level for each gene in a stromal-1 signature and in a stromal-2 signature. The subject&#39;s stromal-1 signature value and stromal-2 signature value are then derived from the gene expression profile. The stromal-1 signature value is subtracted from the stomal-2 signature value to thereby obtain the subject&#39;s stromal score. The subject&#39;s stromal score is evaluated to determine whether it is higher or lower than a standard stromal score. If the subject&#39;s stromal score is higher than the standard stromal score, then antiangiogenic therapy is indicated, and the subject can be treated with antiangiogenic therapy. If the subject&#39;s stromal score is not higher than the standard stromal-score, then antiangiogenic therapy is not indicated. 
     Additionally, the invention provides a machine-readable medium containing a digitally encoded GCB signature value, a digitally encoded stromal-1 signature value, a digitally encoded stromal-2 signature, or any combination of the foregoing signature values obtained from a subject suffering from DLBCL. 
     In another embodiment the invention provides a machine-readable medium containing the digitally encoded survival predictor score obtained using a method disclosed herein for predicting the survival outcome of a subject suffering from diffuse large B cell lymphoma (DLBCL). In yet another embodiment, the invention provides a machine-readable medium containing the survival estimate curve obtained using a method disclosed herein for generating a survival estimate curve for subjects suffering from DLBCL. In still another embodiment, the invention provides a machine-readable medium containing the digitally encoded probability of survival calculated according to a method disclosed herein for predicting the survival outcome (e.g., progression-free survival or overall survival) of a subject suffering from DLBCL. Furthermore, the invention provides a machine-readable medium containing the digitally encoded stromal score generated by a method disclosed herein for evaluating a subject for antiangiogenic therapy of DLBCL. 
     The invention also provides a targeted array comprising at least one probe or at least one set of probes for each gene in a germinal center B cell gene (GCB) expression signature, a stromal-1 gene expression signature, and a stromal-2 gene expression signature. The array can include probes for fewer than 20,000 genes or fewer than 10,000 genes. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  is a Kaplan-Meier estimates plot depicting the probability of progression-free-survival versus time (in years) of patients with GCB DLBCL and ABC DLBCL. The plot indicates that GCB patients have a more favorable, i.e., higher probability of progression-free survival rate than ABC patients for at least five years following R-CHOP therapy. 
         FIG. 1B  a Kaplan-Meier estimates plot depicting the probability of overall survival versus time (in years) of patients with GCB DLBCL and ABC DLBCL. The plot indicates that GCB patients have a more favorable, i.e., higher probability, of overall survival than ABC patients for at least five years following R-CHOP therapy. 
         FIG. 1C  is a series of four Kaplan-Meier estimates plots depicting the probabilities of overall survival versus time (in years) in DLBCL patients. Each of the four plots correlates the probability of overall survival with the lymph node/stromal-1, germinal center B cell, proliferation, or MHC class II gene expression signature, respectively. Moreover, in each plot, the average expression of the signature genes in each biopsy sample was used to rank cases and divide the cohort into quartile groups as indicated. 
         FIG. 2A  is a pair of Kaplan-Meier estimates plots depicting the probability of progression-free-survival and the probability of overall survival, as indicated, versus time (in years) among DLBCL patients treated with R-CHOP. Patient samples were ranked according to a bivariate model created using the germinal center B cell (GCB) and stromal-1 signatures and divided into quartile groups. 
         FIG. 2B  is a pair of Kaplan-Meier plots depicting the probability of progression-free-survival and the probability of overall survival, as indicated, versus time (in years) among DLBCL patients treated with R-CHOP. Patient samples were ranked according to a survival predictor score derived from a model incorporating the germinal center B cell, stromal-1, and stromal-2 signatures and divided into quartile groups. 
         FIG. 2C  is a series of three Kaplan-Meier estimates plots depicting the probability of overall survival versus time (in years) among R-CHOP treated DLBCL patients in the indicated low, intermediate, or high IPI risk groups. Patient samples were stratified according to the same survival predictor score used in  FIG. 2B , except that the first and second quartiles were merged, and the third and fourth quartiles were merged. 
         FIG. 3  depicts the expression levels of the indicated GCB cell, stromal-1, and stromal-2 signature genes in ABC, GCB, and unclassified DLBCL biopsy samples. Relative levels of gene expression are depicted according to the scale shown. Shown at the bottom are the signature averages for each patient. Also shown is the stromal score, which is the component of the survival model contributed by the difference between the stromal-2 and stromal-1 signature averages. The survival predictor score is shown for each patient and was used to order the cases, after grouping into ABC DLBCL, GCB DLBCL, and unclassified categories. 
         FIG. 4A  depicts the relative gene expression of stromal-1, stromal-2, and germinal center B cell signatures in CD19+ malignant and CD19− non-malignant subpopulations of cells isolated from three biopsy specimens from patients with DLBCL. Stromal-1 and stromal-2 signature genes were more highly expressed in the non-malignant cells, whereas the germinal center B cell signature genes were more highly expressed in the malignant cells. The log 2 ratios of gene expression levels in the CD19− subpopulation to those in the CD19+ subpopulations are depicted according to the scale shown. 
         FIG. 4B  depicts the results of gene enrichment analysis comparing the stromal-1 gene signature with mesenchyme-1 and mesenchyme-2 signatures (from normal mesenchymal origin cells), with a monocyte signature expressed more highly in normal blood monocytes than in blood B, T, and NK cells, and in a pan-T cell signature expressed more highly in blood T cells than in blood B cells, NK cells, and monocytes. While a relationship was seen between stromal-1 signature and mesenchyme-1, mesenchyme-2, and monocyte signatures, no relationship was observed between the stromal-1 signature and a pan-T cell signature expressed more highly in blood T cells than in blood B cells, NK cells, and monocytes. The relative levels of gene expression are depicted according to the scale shown. 
         FIG. 5A  is a Kaplan-Meier estimates plot depicting the probability of overall survival versus time (in years) in DLBCL cases segregated according to SPARC protein expression levels, as indicated. 
         FIG. 5B  is a pair of images showing the identification of tumor blood vessels by immunohistochemical analysis of CD34+ endothelial cells in representative DLBCL biopsies having low or high blood vessel density (CD34+ objects/μM 2 ), as indicated. 
         FIG. 5C  is a plot depicting the correlation between the tumor blood vessel density and the stromal score in analyzed DLBCL biopsies. 
         FIG. 6A  is a Kaplan-Meier estimates plot depicting the probability of overall survival versus time (in years) for “LLMPP CHOP” patients with DLBCL following therapy. The plot indicates that in this cohort, patients with GCB DLBCL show significantly superior overall survival compared to patients with ABC DLBCL following CHOP therapy. 
         FIG. 6B  is a is a Kaplan-Meier estimates plot depicting the probability of overall survival versus time (in years) for “MMMLNP CHOP” patients with DLBCL following therapy. In this cohort, patients with GCB DLBCL show significantly superior overall survival compared to patients with ABC DLBCL following CHOP therapy. 
         FIG. 7  is a set of four Kaplan-Meier estimates plots depicting the probability of overall survival versus time (in years) in a “MMMLNP CHOP” cohort. Each of the four plots correlates the probability of overall survival with the lymph node/stromal-1, germinal center B cell, proliferation, or MHC class II gene expression signature, respectively. Moreover, in each plot, the average expression of the signature genes in each biopsy sample was used to rank cases and divide the cohort into quartile groups as indicated. 
         FIG. 8A  is a Kaplan-Meier estimates plot depicting the probability of overall survival versus time (in years) in a “LLMPP CHOP” cohort, which was divided according to MHC class II signature expression levels. Patients with low MHC class II signature expression have significantly inferior overall survival compared to patients with normal MHC class II expression. 
         FIG. 8B  is a Kaplan-Meier estimates plot depicting the probability of overall survival versus time (in years) in a “MMMLNP CHOP” cohort, which was divided according to MHC class II signature expression levels. Patients with low MHC class II signature expression have significantly inferior overall survival compared to patients with normal MHC class II expression. 
         FIG. 8C  is a Kaplan-Meier estimates plot depicting the probability of overall survival versus time (in years) in a “LLMPP R-CHOP” cohort, which was divided according to MHC class II signature expression levels. There was no significant difference in the overall survival of patients with low MHC class II signature expression as compared to patients with normal MHC class II expression. 
         FIG. 9A  is a pair of Kaplan-Meier estimates plots depicting the probabilities of progression-free survival or overall survival, as indicated, versus time (in years) among patients grouped into quartiles according to a gene expression model consisting of stromal-1 signature, GCB signature, and signature 122 following R-CHOP therapy. 
         FIG. 9B  is a pair Kaplan-Meier estimates plots depicting the probabilities of overall survival versus time (in years) among “MMMLNP CHOP” cohort patients grouped into quartiles according to a gene expression model consisting of either stromal-1 signature and GCB signature or stromal-1, GCB signature, and signature 122, as indicated, following CHOP therapy. 
         FIG. 9C  is a Kaplan-Meier estimates plot depicting the probabilities of overall survival versus time (in years) among “MMMLNP CHOP” cohort patients grouped into quartiles according to a gene expression model consisting of stromal-1 signature, GCB signature, and stromal-2 signature following CHOP therapy. 
         FIG. 10A  is a Kaplan-Meier estimates plot depicting the overall survival among low revised International Prognostic Index (IPI) risk group patients stratified according to the gene expression-based outcome predictor score. After grouping patients into quartiles according to gene expression-based outcome predictor score, quartiles 1 and 2 were merged (Low Model Score), and quartiles 3 and 4 were merged (High Model Score). 
         FIG. 10B  is a Kaplan-Meier estimates plot depicting the overall survival among intermediate revised International Prognostic Index (IPI) risk group patients stratified according to the gene expression-based outcome predictor. After grouping patients into quartiles according to gene expression-based outcome predictor score, quartiles 1 and 2 were merged (Low Model Score), and quartiles 3 and 4 were merged (High Model Score). 
         FIG. 10C  is a Kaplan-Meier estimates plot depicting the overall survival among high revised International Prognostic Index (IPI) risk group patients stratified according to the gene expression-based outcome predictor. After grouping patients into quartiles according to gene expression-based outcome predictor score, quartiles 1 and 2 were merged (Low Model Score), and quartiles 3 and 4 were merged (High Model Score). 
         FIG. 11  depicts normal mesenchymal-1 and normal mesenchymal-2 signature gene expression in various normal tissues. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention provides a gene expression-based survival predictor for DLBCL patients, including those patients receiving the current standard of care, R-CHOP. The survival predictor can be used to determine the relative probability of a survival outcome in a specific subject. The survival predictor can also be used to predict; i.e., determine the expected probability that a survival outcome will occur by a defined period following treatment for DLBCL. Such prognostic information can be very useful to both the patient and the physician. Patients with survival predictor scores that indicate inferior outcome with R-CHOP therapy could be candidates for a different therapeutic regimen, if, for example, they relapse from R-CHOP treatment. The survival predictor can also be used in the design of clinical studies and analysis of clinical data to provide a quantitative survey of the types of DLBCL patients from which clinical data was gathered. The predictor can be used to improve one or more comparisons between data from different sources (e.g., from different clinical trials), by enabling comparisons with respect to patient characteristics, which are manifested in the gene expression levels that determine and, thus, are embodied in the predictor. Furthermore, the invention provides information that can be very valuable to a DLBCL patient, since the patient may be inclined to order his or her life quite differently, depending on whether the patient has a high or low probability of surviving and/or remaining progression-free for a period of time following treatment. 
     The following abbreviations are used herein: ABC, activated B cell-like diffuse large B cell lymphoma; CHOP, cyclophosphamide, doxorubicine, vincristine, and prednisone; CI, confidence interval; COP, cyclophosphamide, vincristine, and prednisone; DLBCL, diffuse large B cell lymphoma; DOD, dead of disease; ECOG, Eastern Cooperative Oncology Group; FACS, fluorescence-activated cell sorting; FH, follicular hyperplasia; FISH, fluorescence in situ hybridization; FL, follicular lymphoma; GC, geiminal center; GCB, germinal center B cell-like diffuse large B cell lymphoma; IPI, International Prognostic Index; LPC, lymphoplasmacytic lymphoma; MHC, major histocompatibility complex; NA, not available or not applicable; NK, natural killer; PCR, polymerase chain reaction; RQ-PCR, real-time quantitative PCR; RT-PCR, reverse transcriptase polymerase chain reaction; SAGE, serial analysis of gene expression; WHO, World Health Organization. 
     The term “R-CHOP” as used herein refers generally to any therapeutic regimen that includes chemotherapy and the administration of Rituximab. Accordingly, while the term can refer to a Rituximab combination therapy that includes a CHOP regimen of cyclophosphamide, doxorubicine, vincristine, and prednisone, the term R-CHOP can also refer to therapy that includes Rituximab in combination with a chemotherapeutic regimen other than CHOP. 
     The phrase “gene expression data” as well as “gene expression level” as used herein refers to information regarding the relative or absolute level of expression of a gene or set of genes in a cell or group of cells. The level of expression of a gene may be determined based on the level of RNA, such as mRNA, encoded by the gene. Alternatively, the level of expression may be determined based on the level of a polypeptide or fragment thereof encoded by the gene. Gene expression data may be acquired for an individual cell, or for a group of cells such as a tumor or biopsy sample. Gene expression data and gene expression levels can be stored on computer readable media, e.g., the computer readable medium used in conjunction with a microarray or chip reading device. Such gene expression data can be manipulated to generate gene expression signatures. 
     The term “microarray,” “array,” or “chip” refers to a plurality of nucleic acid probes coupled to the surface of a substrate in different known locations. The substrate is preferably solid. Microarrays have been generally described in the art in, for example, U.S. Pat. No. 5,143,854 (Pirrung), U.S. Pat. No. 5,424,186 (Fodor), U.S. Pat. No. 5,445,934 (Fodor), U.S. Pat. No. 5,677,195 (Winkler), U.S. Pat. No. 5,744,305 (Fodor), U.S. Pat. No. 5,800,992 (Fodor), and U.S. Pat. No. 6,040,193 (Winkler), and Fodor et al.,  Science,  251: 767-777 (1991). 
     The term “gene expression signature” or “signature” as used herein refers to a group of coordinately expressed genes. The genes making up this signature may be expressed in a specific cell lineage, stage of differentiation, or during a particular biological response. The genes can reflect biological aspects of the tumors in which they are expressed, such as the cell of origin of the cancer, the nature of the non-malignant cells in the biopsy, and the oncogenic mechanisms responsible for the cancer (Shaffer et al.,  Immunity,  15: 375-385 (2001)). Examples of gene expression signatures include lymph node, proliferation (Rosenwald et al.,  New Engl. J. Med.,  346: 1937-1947 (2002)), MHC class II, ABC DLBCL high, B cell differentiation, T-cell, macrophage, immune response-1, and immune response-2 signatures (U.S. Patent Application Publication No. 2007/0105136 (Staudt)). 
     The term “signature value” as used herein corresponds to a mathematical combination of measurements from expression levels of the genes in a gene expression signature. An exemplary signature value is a signature average which corresponds to the average or mean of the individual expression levels in a gene expression signature. 
     The phrase “survival predictor score” as used herein refers to a score generated by a multivariate model used to predict survival based on gene expression. A subject with a higher survival predictor score is predicted to have poorer survival than a subject with a lower survival predictor score. 
     The term “survival” or “overall survival” as used herein may refer to the probability or likelihood of a subject surviving for a particular period of time. Alternatively, it may refer to the likely term of survival for a subject, such as expected mean or median survival time for a subject with a particular gene expression pattern. 
     The term “progression free survival” as used herein can refer to the probability or likelihood of a subject surviving without significant progression or worsening of disease for a particular period of time. Alternatively, it may refer to the likely term for a subject of survival without significant progression or worsening of disease, such as expected mean or median survival time for a subject with a particular gene expression pattern without significant progression or worsening of disease. 
     The term “survival outcome” as used herein may refer to survival, overall survival, or progression free survival. 
     The phrase “scale factor” as used herein refers to a factor that relates change in gene expression to prognosis. An example of a scale factor is a factor obtained by maximizing the partial likelihoods of the Cox proportional hazards model. 
     The gene expression signatures, signature values, survival predictor scores, stromal scores, survival estimate curves, and probabilities of survival disclosed herein may be stored in digitally encoded format on computer readable media, e.g., computer readable media used in conjunction with microarray or chip reading devices or computer readable media used to store patient data during treatment for DLBCL. Such media and the specialized devices that use them, e.g., for diagnostic and clinical applications, are known in the art. 
     The invention provides a method for predicting a survival outcome in a subject diagnosed with DLBCL using gene expression data. Such data may be gathered using any effective method of quantifying gene expression. For example, gene expression data may be measured or estimated using one or more microarrays. The microarrays may be of any effective type, including, but not limited to, nucleic acid based or antibody based. Gene expression may also be measured by a variety of other techniques, including, but not limited to, PCR, quantitative RT-PCR, real-time PCR, RNA amplification, in situ hybridization, immunohistochemistry, immunocytochemistry, FACS, serial analysis of gene expression (SAGE) (Velculescu et al.,  Science,  270: 484-87 (1995)), Northern blot hybridization, or western blot hybridization. 
     Nucleic acid microarrays generally comprise nucleic acid probes derived from individual genes and placed in an ordered array on a support. This support may be, for example, a glass slide, a nylon membrane, or a silicon wafer. Gene expression patterns in a sample are obtained by hybridizing the microarray with the gene expression product from the sample. This gene expression product may be, for example, total cellular mRNA, rRNA, or cDNA obtained by reverse transcription of total cellular mRNA. The gene expression product from a sample is labeled with a radioactive, fluorescent, or other label to allow for detection. Following hybridization, the microarray is washed, and hybridization of the gene expression product to each nucleic acid probe on the microarray is detected and quantified using a detection device such as a phosphorimager or scanning confocal microscope. 
     There are two broad classes of microarrays: cDNA and oligonucleotide arrays. cDNA arrays consist of hundreds or thousands of cDNA probes immobilized on a solid support. These cDNA probes are usually 100 nucleotides or greater in size. There are two commonly used designs for cDNA arrays. The first is the nitrocellulose filter array, which is generally prepared by robotic spotting of purified DNA fragments or lysates of bacteria containing cDNA clones onto a nitrocellulose filter (Southern et al.,  Genomics,  13: 1008-17 (1992); Southern et al.,  Nucl Acids Res  22: 1368-73 (1994); Gress et al.,  Oncogene,  13: 1819-30 (1996); Pietu et al.,  Genome Res.,  6: 492-503 (1996)). The other commonly used cDNA arrays is fabricated by robotic spotting of PCR fragments from cDNA clones onto glass microscope slides (Schena et al.,  Science,  270: 467-70 (1995); DeRisi et al.,  Nature Genet.,  14: 457-60 (1996); Schena et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  93: 10614-19 (1996); Shalon et al.,  Genome Res.,  6: 639-45 (1996); DeRisi et al.,  Science,  278: 680-86 (1997); Heller et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  94: 2150-55 (1997); Lashkari et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  94: 13057-62 (1997)). These cDNA microarrays are simultaneously hybridized with two fluorescent cDNA probes, each labeled with a different fluorescent dye (typically Cy3 or Cy5). In this format, the relative mRNA expression in two samples is directly compared for each gene on the microarray. Oligonucleotide arrays differ from cDNA arrays in that the probes are 20- to 25-mer oligonucleotides. Oligonucleotide arrays are generally produced by in situ oligonucleotide synthesis in conjunction with photolithographic masking techniques (Pease et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  91: 5022-26 (1994); Lipshutz et al.,  Biotechniques  19: 442-47 (1995); Chee et al.,  Science,  274: 610-14 (1996); Lockhart et al.,  Nature Biotechnol.,  14: 1675-80 (1996); Wodicka et al.,  Nature Biotechnol.,  15: 1359-6714 (1997)). The solid support for oligonucleotide arrays is typically a glass or silicon surface. 
     Methods and techniques applicable to array synthesis and use have been described in, for example, U.S. Pat. No. 5,143,854 (Pirrung), U.S. Pat. No. 5,242,974 (Holmes), U.S. Pat. No. 5,252,743 (Barrett), U.S. Pat. No. 5,324,633 (Fodor), U.S. Pat. No. 5,384,261 (Winkler), U.S. Pat. No. 5,424,186 (Fodor), U.S. Pat. No. 5,445,934 (Fodor), U.S. Pat. No. 5,451,683 (Barrett), U.S. Pat. No. 5,482,867 (Barrett), U.S. Pat. No. 5,491,074 (Aldwin), U.S. Pat. No. 5,527,681 (Holmes), U.S. Pat. No. 5,550,215 (Holmes), U.S. Pat. No. 5,571,639 (Hubbell), U.S. Pat. No. 5,578,832 (Trulson), U.S. Pat. No. 5,593,839 (Hubbell), U.S. Pat. No. 5,599,695 (Pease), U.S. Pat. No. 5,624,711 (Sundberg), U.S. Pat. No. 5,631,734 (Stem), U.S. Pat. No. 5,795,716 (Chee), U.S. Pat. No. 5,831,070 (Pease), U.S. Pat. No. 5,837,832 (Chee), U.S. Pat. No. 5,856,101 (Hubbell), U.S. Pat. No. 5,858,659 (Sapolsky), U.S. Pat. No. 5,936,324 (Montagu), U.S. Pat. No. 5,968,740 (Fodor), U.S. Pat. No. 5,974,164 (Chee), U.S. Pat. No. 5,981,185 (Matson), U.S. Pat. No. 5,981,956 (Stem), U.S. Pat. No. 6,025,601 (Trulson), U.S. Pat. No. 6,033,860 (Lockhart), U.S. Pat. No. 6,040,193 (Winkler), U.S. Pat. No. 6,090,555 (Fiekowsky), and U.S. Pat. No. 6,410,229 (Lockhart), and U.S. Patent Application Publication No. 2003/0104411 (Fodor). 
     Microarrays may generally be produced using a variety of techniques, such as mechanical or light directed synthesis methods that incorporate a combination of photolithographic methods and solid phase synthesis methods. Techniques for the synthesis of microarrays using mechanical synthesis methods are described in, for example, U.S. Pat. No. 5,384,261 (Winkler) and U.S. Pat. No. 6,040,193 (Winkler). Although a planar array surface is preferred, the microarray may be fabricated on a surface of virtually any shape, or even on a multiplicity of surfaces. Microarrays may be nucleic acids on beads, gels, polymeric surfaces, fibers such as fiber optics, glass, or any other appropriate substrate. See, for example, U.S. Pat. No. 5,708,153 (Dower), U.S. Pat. No. 5,770,358 (Dower), U.S. Pat. No. 5,789,162 (Dower), U.S. Pat. No. 5,800,992 (Fodor), and U.S. Pat. No. 6,040,193 (Winkler). 
     Microarrays can be packaged in such a manner as to allow for diagnostic use, or they can be all-inclusive devices. See, for example, U.S. Pat. No. 5,856,174 (Lipshutz) and U.S. Pat. No. 5,922,591 (Anderson). 
     Microarrays directed to a variety of purposes are commercially available from Affymetrix (Santa Clara, Calif.). For instance, these microarrays may be used for genotyping and gene expression monitoring. 
     Gene expression data can be used to identify genes that are coordinately regulated. Genes that encode components of the same multi-subunit protein complex are often coordinately regulated. Coordinate regulation is also observed among genes whose products function in a common differentiation program or in the same physiological response pathway. Recent application of gene expression profiling to the immune system has shown that lymphocyte differentiation and activation are accompanied by parallel changes in expression among hundreds of genes. Gene expression databases may be used to interpret the pathological changes in gene expression that accompany autoimmunity, immune deficiencies, cancers of immune cells and of normal immune responses. 
     Scanning and interpreting large bodies of relative gene expression data is a formidable task. This task is greatly facilitated by algorithms designed to organize the data in a way that highlights systematic features, and by visualization tools that represent the differential expression of each gene as varying intensities and hues of color (Eisen et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  95: 14863-68 (1998)). The development of microarrays, which are capable of generating massive amounts of expression data in a single experiment, has greatly increased the need for faster and more efficient methods of analyzing large-scale expression data sets. In order to effectively utilize microarray gene expression data for the prediction of survival in DLBCL patients, there is a need for new algorithms to be developed, which can identify important information and convert it to a more manageable format. In addition, the microarrays used to generate this data can be streamlined to incorporate probe sets that are useful for survival outcome prediction. 
     Mathematical analysis of gene expression data is a rapidly evolving science based on a rich mathematics of pattern recognition developed in other contexts (Kohonen,  Self - Organizing Maps , Springer Press (Berlin 1997)). Mathematical analysis of gene expression data can be used, for example, to identify groups of genes that are coordinately regulated within a biological system, to recognize and interpret similarities between biological samples on the basis of similarities in gene expression patterns, and/or to recognize and identify those features of a gene expression pattern that are related to distinct biological processes or phenotypes. 
     Mathematical analysis of gene expression data often begins by establishing the expression pattern for each gene on an array across a number (n) of experimental samples. The expression pattern of each gene can be represented by a point in n-dimensional space, with each coordinate specified by an expression measurement in one of the n samples (Eisen et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  95: 14863-68 (1998)). A clustering algorithm that uses distance metrics can then be applied to locate clusters of genes in this n-dimensional space. These clusters indicate genes with similar patterns of variation in expression over a series of experiments. Clustering methods that have been applied to microarray data in the past include hierarchical clustering (Eisen et al., supra), self-organizing maps (SOMs) (Tamayo et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  96: 2907-12 (1999)), k-means (Tavazoie et al.,  Nature Genet.,  22: 281-85 (1999)), and deterministic annealing (Alon et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  96: 6745-50 (1999)). 
     A variety of different algorithms, each emphasizing distinct orderly features of the data, may be required to glean the maximal biological insight from a set of samples (Alizadeh et al.,  J. Clin. Immunol.,  18: 373-79 (1998)). One such algorithm, hierarchical clustering, begins by determining the gene expression correlation coefficients for each pair of the n genes studied. Genes with similar gene expression correlation coefficients are grouped next to one another in a hierarchical fashion. Generally, genes with similar expression patterns under a particular set of conditions can encode protein products with related roles in the physiological adaptation to those conditions. Novel genes of unknown function that are clustered with a large group of functionally related genes likely participate in similar or related biological process. Likewise, other clustering methods mentioned herein can also group genes together that encode proteins with related biological function. 
     In such clustering methods, genes that are clustered together reflect a particular biological function, and are termed gene expression signatures (Shaffer et al.,  Immunity  15: 375-85 (2001)). One general type of gene expression signature includes genes that are characteristically expressed in a particular cell type or at a particular stage of cellular differentiation or activation. Another general type of gene expression signature includes genes that are regulated in their expression by a particular biological process such as proliferation, or by the activity of a particular transcription factor or signaling pathway. 
     The pattern of gene expression in a biological sample can provide a distinctive and accessible molecular picture of its functional state and identity (DeRisi et al.,  Science,  278: 680-86 (1997); Cho et al.,  Mol. Cell.,  2: 65-73 (1998); Chu et al.,  Science,  282: 699-705 (1998); Holstege et al.,  Cell.,  95: 717-728 (1998); Spellman et al.,  Mol. Biol. Cell,  9: 3273-97 (1998)). Each cell transduces variations in its environment, internal state, and developmental state into readily measured and recognizable variations in its gene expression patterns. Two different samples with related gene expression patterns are therefore likely to be biologically and functionally similar to one another. Thus, a specific gene expression signature in a sample can provide important biological insights into its cellular composition and the function of various intracellular pathways within those cells. 
     Databases of gene expression signatures have proven useful in elucidating the complex gene expression patterns of various cancers. For example, the expression pattern of genes in the germinal center B cell signature in a lymphoma biopsy indicates that the lymphoma includes cells derived from the germinal center stage of differentiation. In the same lymphoma biopsy, the expression of genes from the T cell signature can be used to estimate the degree of infiltration of the tumor by host T cells, while the expression of genes from the proliferation signature can be used to quantitate the tumor cell proliferation rate. In this manner, gene expression signatures provide an “executive summary” of the biological properties of a tumor specimen. Gene expression signatures can also be helpful in interpreting the results of a supervised analysis of gene expression data. A supervised analysis generates a list of genes with expression patterns that correlate with survival. Gene expression signatures can be useful in assigning these “predictive” genes to functional categories. In building a multivariate model of survival based on gene expression data, this functional categorization helps to limit the inclusion of multiple genes in the model that measure the same aspect of tumor biology. 
     This following approach was utilized to create the survival prediction models for DLBCL of the invention. Gene expression profiles were used to create multivariate models for predicting survival. The methods for creating these models were “supervised” in that they used clinical data to guide the selection of genes to be used in the prognostic classification. The method identified genes with expression patterns that correlated with the length of overall survival following chemotherapy. Generally the process for identifying the multivariate model for predicting survival included the following steps:
         1. Genes were identified having expression patterns univariately associated with a particular clinical outcome using a Cox proportional hazards model. Generally, a univariate p-value of &lt;0.01 is considered the cut-off for significance (however, another criterion can be used). These genes were termed “predictor” genes.   2. Within a set of predictor genes, gene expression signatures were identified.   3. For each gene expression signature significantly associated with survival, the average expression of each component genes within this signature was used to generate a gene expression signature value.   4. A multivariate Cox model of clinical outcome using the gene expression signature values was built.   5. Additional genes were added to the model, which added to the statistical power of the model.       

     The model of the invention generates a survival predictor score, with a higher score being associated with worse clinical outcome. The resulting model can be used separately to predict a survival outcome. Alternatively, the model can be used in conjunction with one or more other models, disclosed herein or in other references, to predict a survival outcome. 
     The present invention discloses several gene expression signatures related to the clinical outcome of DLBCL patients. The signatures were identified using the clinical data and methods described below in Examples 1 and 2. Three of these gene expression signatures are the germinal center B cell (GCB) signature, the stromal-1 signature, and the stromal-2 signature. Each component gene of these signatures is identified in Table 1 according to its GenBank accession number, its GeneID assigned by Entrez Gene, a common gene symbol, and a descriptive gene title. Table 1 also provides the Affymetrix Probe Set ID, which can be used (e.g., on the Affymetrix U133+ (Affymetrix, Santa Clara, Calif.) microarray) to determine the gene expression level for the indicated gene. The computer-readable sequence listing filed herewith includes a representative fragment sequence (of about 100 bp or greater) for each genomic target sequence listed in Table 1, followed by the sequence for each probe in the corresponding Affymetrix probe set listed in Table 1. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                 GenBank 
                 Entrez 
                   
                   
                 Affymetrix 
               
               
                 Signature 
                 Accession No. 
                 GeneID 
                 Gene Symbol 
                 Gene Title 
                 Probe Set ID 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 GCB 
                 NM_052932 
                 114908 
                 TMEM123 
                 transmembrane protein 
                 211967_at 
               
               
                   
                   
                   
                   
                 123 
               
               
                 GCB 
                 NM_001014380 
                 84056 
                 KATNAL1 
                 katanin p60 subunit A-like 1 
                 227713_at 
               
               
                 GCB 
                 NM_004665 
                 8875 
                 VNN2 
                 vanin 2 
                 205922_at 
               
               
                 GCB 
                 NM_004760 
                 9263 
                 STK17A 
                 serine/threonine kinase 
                 202693_s_at 
               
               
                   
                   
                   
                   
                 17a (apoptosis-inducing) 
               
               
                 GCB 
                 CR590554 
                   
                   
                 Full-length cDNA clone 
                 228464_at 
               
               
                   
                   
                   
                   
                 CS0DF007YJ21 of Fetal 
               
               
                   
                   
                   
                   
                 brain of Homo sapiens 
               
               
                   
                   
                   
                   
                 (human) 
               
               
                 GCB 
                 NM_017599 
                 55591 
                 VEZT 
                 vezatin, adherens 
                 223089_at 
               
               
                   
                   
                   
                   
                 junctions transmembrane 
               
               
                   
                   
                   
                   
                 protein 
               
               
                 GCB 
                 NM_018351 
                 55785 
                 FGD6 
                 FYVE, RhoGEF and PH 
                 1555136_at 
               
               
                   
                   
                   
                   
                 domain containing 6 
               
               
                 GCB 
                 NM_001007075 
                 51088 
                 KLHL5 
                 kelch-like 5 ( Drosophila ) 
                 226001_at 
               
               
                 GCB 
                 NM_004845 
                 9468 
                 PCYT1B 
                 phosphate 
                 228959_at 
               
               
                   
                   
                   
                   
                 cytidylyltransferase 1, 
               
               
                   
                   
                   
                   
                 choline, beta 
               
               
                 GCB 
                 AK026881 
                   
                   
                 CDNA: FLJ23228 fis, 
                 226799_at 
               
               
                   
                   
                   
                   
                 clone CAE06654 
               
               
                 GCB 
                 NM_018440 
                 55824 
                 PAG1 
                 phosphoprotein 
                 225626_at 
               
               
                   
                   
                   
                   
                 associated with 
               
               
                   
                   
                   
                   
                 glycosphingolipid 
               
               
                   
                   
                   
                   
                 microdomains 1 
               
               
                 GCB 
                 NM_004965 
                 3150 
                 HMGN1 
                 high-mobility group 
                 200944_s_at 
               
               
                   
                   
                   
                   
                 nucleosome binding 
               
               
                   
                   
                   
                   
                 domain 1 
               
               
                 GCB 
                 NM_001706 
                 604 
                 BCL6 
                 B cell CLL/lymphoma 6 
                 228758_at 
               
               
                   
                   
                   
                   
                 (zinc finger protein 51) 
               
               
                 GCB 
                 NM_020747 
                 57507 
                 ZNF608 
                 zinc finger protein 608 
                 229817_at 
               
               
                 GCB 
                 NM_001001695 
                 400941 
                 FLJ42418 
                 FLJ42418 protein 
                 231455_at 
               
               
                 GCB 
                 NM_015055 
                 23075 
                 SWAP70 
                 SWAP-70 protein 
                 209306_s_at 
               
               
                 GCB 
                 NM_005607 
                 5747 
                 PTK2 
                 PTK2 protein tyrosine 
                 208820_at 
               
               
                   
                   
                   
                   
                 kinase 2 
               
               
                 GCB 
                 XM_027236 
                 23508 
                 TTC9 
                 tetratricopeptide repeat 
                 213172_at 
               
               
                   
                   
                   
                   
                 domain 9 
               
               
                 GCB 
                 BQ213652 
                 440864 
                 LOC440864 
                 hypothetical gene 
                 1569034_a_at 
               
               
                   
                   
                   
                   
                 supported by BC040724 
               
               
                 GCB 
                 NM_005574 
                 4005 
                 LMO2 
                 LIM domain only 2 
                 204249_s_at 
               
               
                   
                   
                   
                   
                 (rhombotin-like 1) 
               
               
                 GCB 
                 NM_014667 
                 9686 
                 VGLL4 
                 vestigial like 4 
                 212399_s_at 
               
               
                   
                   
                   
                   
                 ( Drosophila ) 
               
               
                 GCB 
                 NM_002221 
                 3707 
                 ITPKB 
                 inositol 1,4,5- 
                 203723_at 
               
               
                   
                   
                   
                   
                 trisphosphate 3-kinase B 
               
               
                 GCB 
                 NM_000902 
                 4311 
                 MME 
                 membrane metallo- 
                 203434_s_at 
               
               
                   
                   
                   
                   
                 endopeptidase (neutral 
               
               
                   
                   
                   
                   
                 endopeptidase, 
               
               
                   
                   
                   
                   
                 enkephalinase) 
               
               
                 GCB 
                 NM_012446 
                 23635 
                 SSBP2 
                 single-stranded DNA 
                 203787_at 
               
               
                   
                   
                   
                   
                 binding protein 2 
               
               
                 GCB 
                 NM_024613 
                 79666 
                 PLEKHF2 
                 pleckstrin homology 
                 222699_s_at 
               
               
                   
                   
                   
                   
                 domain containing, family 
               
               
                   
                   
                   
                   
                 F (with FYVE domain) 
               
               
                   
                   
                   
                   
                 member 2 
               
               
                 GCB 
                 AV705976 
                   
                   
                 Transcribed locus 
                 204681_s_at 
               
               
                 GCB 
                 NM_012108 
                 26228 
                 BRDG1 
                 BCR downstream 
                 220059_at 
               
               
                   
                   
                   
                   
                 signaling 1 
               
               
                 GCB 
                 NM_014397 
                 10783 
                 NEK6 
                 NIMA (never in mitosis 
                 223158_s_at 
               
               
                   
                   
                   
                   
                 gene a)-related kinase 6 
               
               
                 GCB 
                 NM_018981 
                 54431 
                 DNAJC10 
                 DnaJ (Hsp40) homolog, 
                 225174_at 
               
               
                   
                   
                   
                   
                 subfamily C, member 10 
               
               
                 GCB 
                 NM_001379 
                 1786 
                 DNMT1 
                 DNA (cytosine-5-)- 
                 227684_at 
               
               
                   
                   
                   
                   
                 methyltransferase 1 
               
               
                 GCB 
                 NM_006152 
                 4033 
                 LRMP 
                 lymphoid-restricted 
                 35974_at 
               
               
                   
                   
                   
                   
                 membrane protein 
               
               
                 GCB 
                 NM_024701 
                 79754 
                 ASB13 
                 ankyrin repeat and SOCS 
                 218862_at 
               
               
                   
                   
                   
                   
                 box-containing 13 
               
               
                 GCB 
                 NM_006085 
                 10380 
                 BPNT1 
                 3′(2′), 5′-bisphosphate 
                 232103_at 
               
               
                   
                   
                   
                   
                 nucleotidase 1 
               
               
                 GCB 
                 NM_023009 
                 65108 
                 MARCKSL1 
                 MARCKS-like 1 
                 200644_at 
               
               
                 GCB 
                 NM_033121 
                 88455 
                 ANKRD13A 
                 ankyrin repeat domain 
                 224810_s_at 
               
               
                   
                   
                   
                   
                 13A 
               
               
                 GCB 
                 NM_015187 
                 23231 
                 KIAA0746 
                 KIAA0746 protein 
                 235353_at 
               
               
                 GCB 
                 NM_175739 
                 327657 
                 SERPINA9 
                 serpin peptidase inhibitor, 
                 1553499_s_at 
               
               
                   
                   
                   
                   
                 clade A (alpha-1 
               
               
                   
                   
                   
                   
                 antiproteinase, 
               
               
                   
                   
                   
                   
                 antitrypsin), member 9 
               
               
                 GCB 
                 NM_001012391 
                 400509 
                 RUNDC2B 
                 RUN domain containing 
                 1554413_s_at 
               
               
                   
                   
                   
                   
                 2B 
               
               
                 GCB 
                 XM_034274 
                 4603 
                 MYBL1 
                 v-myb myeloblastosis 
                 213906_at 
               
               
                   
                   
                   
                   
                 viral oncogene homolog 
               
               
                   
                   
                   
                   
                 (avian)-like 1 
               
               
                 Stromal-1 
                 NM_024579 
                 79630 
                 C1orf54 
                 chromosome 1 open 
                 219506_at 
               
               
                   
                   
                   
                   
                 reading frame 54 
               
               
                 Stromal-1 
                 NM_001645 
                 341 
                 APOC1 
                 apolipoprotein C-I 
                 213553_x_at 
               
               
                 Stromal-1 
                 NM_001562 
                 3606 
                 IL18 
                 interleukin 18 (interferon- 
                 206295_at 
               
               
                   
                   
                   
                   
                 gamma-inducing factor) 
               
               
                 Stromal-1 
                 NM_014479 
                 27299 
                 ADAMDEC1 
                 ADAM-like, decysin 1 
                 206134_at 
               
               
                 Stromal-1 
                 NM_003465 
                 1118 
                 CHIT1 
                 chitinase 1 
                 208168_s_at 
               
               
                   
                   
                   
                   
                 (chitotriosidase) 
               
               
                 Stromal-1 
                 NM_000954 
                 5730 
                 PTGDS 
                 prostaglandin D2 
                 211748_x_at 
               
               
                   
                   
                   
                   
                 synthase 21 kDa (brain) 
               
               
                 Stromal-1 
                 NM_001056 
                 6819 
                 SULT1C1 
                 sulfotransferase family, 
                 211470_s_at 
               
               
                   
                   
                   
                   
                 cytosolic, 1C, member 1 
               
               
                 Stromal-1 
                 NM_018000 
                 55686 
                 MREG 
                 melanoregulin 
                 219648_at 
               
               
                 Stromal-1 
                 NM_001018058 
                 22797 
                 TFEC 
                 transcription factor EC 
                 206715_at 
               
               
                 Stromal-1 
                 NM_000239 
                 4069 
                 LYZ 
                 lysozyme (renal 
                 213975_s_at 
               
               
                   
                   
                   
                   
                 amyloidosis) 
               
               
                 Stromal-1 
                 NM_006834 
                 10981 
                 RAB32 
                 RAB32, member RAS 
                 204214_s_at 
               
               
                   
                   
                   
                   
                 oncogene family 
               
               
                 Stromal-1 
                 NM_000416 
                 3459 
                 IFNGR1 
                 interferon gamma 
                 202727_s_at 
               
               
                   
                   
                   
                   
                 receptor 1 
               
               
                 Stromal-1 
                 NM_004666 
                 8876 
                 VNN1 
                 vanin 1 
                 205844_at 
               
               
                 Stromal-1 
                 NM_031491 
                 83758 
                 RBP5 
                 retinol binding protein 5, 
                 223820_at 
               
               
                   
                   
                   
                   
                 cellular 
               
               
                 Stromal-1 
                 NM_001276 
                 1116 
                 CHI3L1 
                 chitinase 3-like 1 
                 209396_s_at 
               
               
                   
                   
                   
                   
                 (cartilage glycoprotein-39) 
               
               
                 Stromal-1 
                 NM_138434 
                 113763 
                 C7orf29 
                 chromosome 7 open 
                 227598_at 
               
               
                   
                   
                   
                   
                 reading frame 29 
               
               
                 Stromal-1 
                 NM_001005340 
                 10457 
                 GPNMB 
                 glycoprotein 
                 201141_at 
               
               
                   
                   
                   
                   
                 (transmembrane) nmb 
               
               
                 Stromal-1 
                 NM_002294 
                 3920 
                 LAMP2 
                 lysosomal-associated 
                 203041_s_at 
               
               
                   
                   
                   
                   
                 membrane protein 2 
               
               
                 Stromal-1 
                 NM_002888 
                 5918 
                 RARRES1 
                 retinoic acid receptor 
                 221872_at 
               
               
                   
                   
                   
                   
                 responder (tazarotene 
               
               
                   
                   
                   
                   
                 induced) 1 
               
               
                 Stromal-1 
                 NM_172248 
                 1438 
                 CSF2RA 
                 colony stimulating factor 2 
                 210340_s_at 
               
               
                   
                   
                   
                   
                 receptor, alpha, low- 
               
               
                   
                   
                   
                   
                 affinity (granulocyte- 
               
               
                   
                   
                   
                   
                 macrophage) 
               
               
                 Stromal-1 
                 NM_018344 
                 55315 
                 SLC29A3 
                 solute carrier family 29 
                 219344_at 
               
               
                   
                   
                   
                   
                 (nucleoside transporters), 
               
               
                   
                   
                   
                   
                 member 3 
               
               
                 Stromal-1 
                 NM_032413 
                 84419 
                 C15orf48 
                 chromosome 15 open 
                 223484_at 
               
               
                   
                   
                   
                   
                 reading frame 48 
               
               
                 Stromal-1 
                 NM_001001851 
                 80760 
                 ITIH5 
                 inter-alpha (globulin) 
                 1553243_at 
               
               
                   
                   
                   
                   
                 inhibitor H5 
               
               
                 Stromal-1 
                 NM_000211 
                 3689 
                 ITGB2 
                 integrin, beta 2 
                 1555349_a_at 
               
               
                   
                   
                   
                   
                 (complement component 
               
               
                   
                   
                   
                   
                 3 receptor 3 and 4 
               
               
                   
                   
                   
                   
                 subunit) 
               
               
                 Stromal-1 
                 NM_005213 
                 1475 
                 CSTA 
                 cystatin A (stefin A) 
                 204971_at 
               
               
                 Stromal-1 
                 NM_003874 
                 8832 
                 CD84 
                 CD84 molecule 
                 205988_at 
               
               
                 Stromal-1 
                 NM_000228 
                 3914 
                 LAMB3 
                 laminin, beta 3 
                 209270_at 
               
               
                 Stromal-1 
                 NM_005651 
                 6999 
                 TDO2 
                 tryptophan 2,3- 
                 205943_at 
               
               
                   
                   
                   
                   
                 dioxygenase 
               
               
                 Stromal-1 
                 NM_001005266 
                 283651 
                 C15orf21 
                 chromosome 15 open 
                 242649_x_at 
               
               
                   
                   
                   
                   
                 reading frame 21 
               
               
                 Stromal-1 
                 AV659177 
                   
                   
                 Transcribed locus 
                 230391_at 
               
               
                 Stromal-1 
                 NM_001747 
                 822 
                 CAPG 
                 capping protein (actin 
                 201850_at 
               
               
                   
                   
                   
                   
                 filament), gelsolin-like 
               
               
                 Stromal-1 
                 NM_000784 
                 1593 
                 CYP27A1 
                 cytochrome P450, family 
                 203979_at 
               
               
                   
                   
                   
                   
                 27, subfamily A, 
               
               
                   
                   
                   
                   
                 polypeptide 1 
               
               
                 Stromal-1 
                 NM_052998 
                 113451 
                 ADC 
                 arginine decarboxylase 
                 228000_at 
               
               
                 Stromal-1 
                 NM_016240 
                 51435 
                 SCARA3 
                 scavenger receptor class 
                 219416_at 
               
               
                   
                   
                   
                   
                 A, member 3 
               
               
                 Stromal-1 
                 Z74615 
                   
                 COL1A1 
                 Collagen, type I, alpha 1 
                 217430_x_at 
               
               
                 Stromal-1 
                 NM_052947 
                 115701 
                 ALPK2 
                 alpha-kinase 2 
                 228367_at 
               
               
                 Stromal-1 
                 NM_021136 
                 6252 
                 RTN1 
                 reticulon 1 
                 210222_s_at 
               
               
                 Stromal-1 
                 AL049370 
                   
                   
                 Full-length cDNA clone 
                 213100_at 
               
               
                   
                   
                   
                   
                 CL0BB018ZE07 of 
               
               
                   
                   
                   
                   
                 Neuroblastoma of Homo 
               
               
                   
                   
                   
                   
                 sapiens (human) 
               
               
                 Stromal-1 
                 NM_006042 
                 9955 
                 HS3ST3A1 
                 heparan sulfate 
                 219985_at 
               
               
                   
                   
                   
                   
                 (glucosamine) 3-O- 
               
               
                   
                   
                   
                   
                 sulfotransferase 3A1 
               
               
                 Stromal-1 
                 NM_000041 
                 348 
                 APOE 
                 apolipoprotein E 
                 203382_s_at 
               
               
                 Stromal-1 
                 NM_004994 
                 4318 
                 MMP9 
                 matrix metallopeptidase 9 
                 203936_s_at 
               
               
                   
                   
                   
                   
                 (gelatinase B, 92 kDa 
               
               
                   
                   
                   
                   
                 gelatinase, 92 kDa type IV 
               
               
                   
                   
                   
                   
                 collagenase) 
               
               
                 Stromal-1 
                 NM_001831 
                 1191 
                 CLU 
                 clusterin 
                 222043_at 
               
               
                 Stromal-1 
                 NM_002305 
                 3956 
                 LGALS1 
                 lectin, galactoside- 
                 201105_at 
               
               
                   
                   
                   
                   
                 binding, soluble, 1 
               
               
                   
                   
                   
                   
                 (galectin 1) 
               
               
                 Stromal-1 
                 NM_032024 
                 83938 
                 C10orf11 
                 chromosome 10 open 
                 223703_at 
               
               
                   
                   
                   
                   
                 reading frame 11 
               
               
                 Stromal-1 
                 NM_001025201 
                 1123 
                 CHN1 
                 chimerin (chimaerin) 1 
                 212624_s_at 
               
               
                 Stromal-1 
                 NM_003489 
                 8204 
                 NRIP1 
                 nuclear receptor 
                 202599_s_at 
               
               
                   
                   
                   
                   
                 interacting protein 1 
               
               
                 Stromal-1 
                 NM_032646 
                 94015 
                 TTYH2 
                 tweety homolog 2 
                 223741_s_at 
               
               
                   
                   
                   
                   
                 ( Drosophila ) 
               
               
                 Stromal-1 
                 NM_001312 
                 1397 
                 CRIP2 
                 cysteine-rich protein 2 
                 208978_at 
               
               
                 Stromal-1 
                 NM_023075 
                 65258 
                 MPPE1 
                 metallophosphoesterase 1 
                 213924_at 
               
               
                 Stromal-1 
                 NM_004364 
                 1050 
                 CEBPA 
                 CCAAT/enhancer binding 
                 204039_at 
               
               
                   
                   
                   
                   
                 protein (C/EBP), alpha 
               
               
                 Stromal-1 
                 NM_000248 
                 4286 
                 MITF 
                 microphthalmia- 
                 207233_s_at 
               
               
                   
                   
                   
                   
                 associated transcription 
               
               
                   
                   
                   
                   
                 factor 
               
               
                 Stromal-1 
                 NM_002185 
                 3575 
                 IL7R 
                 interleukin 7 receptor 
                 226218_at 
               
               
                 Stromal-1 
                 NM_021638 
                 60312 
                 AFAP 
                 actin filament associated 
                 203563_at 
               
               
                   
                   
                   
                   
                 protein 
               
               
                 Stromal-1 
                 NM_003786 
                 8714 
                 ABCC3 
                 ATP-binding cassette, 
                 208161_s_at 
               
               
                   
                   
                   
                   
                 sub-family C 
               
               
                   
                   
                   
                   
                 (CFTR/MRP), member 3 
               
               
                 Stromal-1 
                   
                 730351 
                 LOC730351 
                 hypothetical protein 
                 229407_at 
               
               
                   
                   
                   
                   
                 LOC730351 
               
               
                 Stromal-1 
                 NM_012153 
                 26298 
                 EHF 
                 ets homologous factor 
                 225645_at 
               
               
                 Stromal-1 
                 NM_004887 
                 9547 
                 CXCL14 
                 chemokine (C—X—C motif) 
                 222484_s_at 
               
               
                   
                   
                   
                   
                 ligand 14 
               
               
                 Stromal-1 
                 NM_002030 
                 2359 
                 FPRL2 
                 formyl peptide receptor- 
                 230422_at 
               
               
                   
                   
                   
                   
                 like 2 
               
               
                 Stromal-1 
                 NM_001321 
                 1466 
                 CSRP2 
                 cysteine and glycine-rich 
                 207030_s_at 
               
               
                   
                   
                   
                   
                 protein 2 
               
               
                 Stromal-1 
                 NM_001945 
                 1839 
                 HBEGF 
                 heparin-binding EGF-like 
                 203821_at 
               
               
                   
                   
                   
                   
                 growth factor 
               
               
                 Stromal-1 
                 NM_031412 
                 23710 
                 GABARAPL1 
                 GABA(A) receptor- 
                 208869_s_at 
               
               
                   
                   
                   
                   
                 associated protein like 1 
               
               
                 Stromal-1 
                 NM_006022 
                 8848 
                 TSC22D1 
                 TSC22 domain family, 
                 215111_s_at 
               
               
                   
                   
                   
                   
                 member 1 
               
               
                 Stromal-1 
                 NM_016174 
                 51148 
                 CEECAM1 
                 cerebral endothelial cell 
                 224794_s_at 
               
               
                   
                   
                   
                   
                 adhesion molecule 1 
               
               
                 Stromal-1 
                 NM_015103 
                 23129 
                 PLXND1 
                 plexin D1 
                 212235_at 
               
               
                 Stromal-1 
                 NM_003270 
                 7105 
                 TSPAN6 
                 tetraspanin 6 
                 209109_s_at 
               
               
                 Stromal-1 
                 NM_000887 
                 3687 
                 ITGAX 
                 integrin, alpha X 
                 210184_at 
               
               
                   
                   
                   
                   
                 (complement component 
               
               
                   
                   
                   
                   
                 3 receptor 4 subunit) 
               
               
                 Stromal-1 
                 NM_001864 
                 1346 
                 COX7A1 
                 cytochrome c oxidase 
                 204570_at 
               
               
                   
                   
                   
                   
                 subunit VIIa polypeptide 1 
               
               
                   
                   
                   
                   
                 (muscle) 
               
               
                 Stromal-1 
                 CR599008 
                   
                 GPR157 
                 Full-length cDNA clone 
                 227970_at 
               
               
                   
                   
                   
                   
                 CS0DJ007YL22 of T cells 
               
               
                   
                   
                   
                   
                 (Jurkat cell line) Cot 10- 
               
               
                   
                   
                   
                   
                 normalized of Homo 
               
               
                   
                   
                   
                   
                 sapiens (human) 
               
               
                 Stromal-1 
                 NM_198580 
                 376497 
                 SLC27A1 
                 solute carrier family 27 
                 226728_at 
               
               
                   
                   
                   
                   
                 (fatty acid transporter), 
               
               
                   
                   
                   
                   
                 member 1 
               
               
                 Stromal-1 
                 NM_025106 
                 80176 
                 SPSB1 
                 splA/ryanodine receptor 
                 226075_at 
               
               
                   
                   
                   
                   
                 domain and SOCS box 
               
               
                   
                   
                   
                   
                 containing 1 
               
               
                 Stromal-1 
                 NM_020130 
                 56892 
                 C8orf4 
                 chromosome 8 open 
                 218541_s_at 
               
               
                   
                   
                   
                   
                 reading frame 4 
               
               
                 Stromal-1 
                 NM_173833 
                 286133 
                 SCARA5 
                 scavenger receptor class 
                 229839_at 
               
               
                   
                   
                   
                   
                 A, member 5 (putative) 
               
               
                 Stromal-1 
                 NM_007223 
                 11245 
                 GPR176 
                 G protein-coupled 
                 227846_at 
               
               
                   
                   
                   
                   
                 receptor 176 
               
               
                 Stromal-1 
                 NM_013437 
                 29967 
                 LRP12 
                 low density lipoprotein- 
                 219631_at 
               
               
                   
                   
                   
                   
                 related protein 12 
               
               
                 Stromal-1 
                 NM_007332 
                 8989 
                 TRPA1 
                 transient receptor 
                 228438_at 
               
               
                   
                   
                   
                   
                 potential cation channel, 
               
               
                   
                   
                   
                   
                 subfamily A, member 1 
               
               
                 Stromal-1 
                 NM_152744 
                 221935 
                 SDK1 
                 sidekick homolog 1 
                 229912_at 
               
               
                   
                   
                   
                   
                 (chicken) 
               
               
                 Stromal-1 
                 NM_001409 
                 1953 
                 MEGF6 
                 multiple EGF-like- 
                 226869_at 
               
               
                   
                   
                   
                   
                 domains 6 
               
               
                 Stromal-1 
                 NM_012082 
                 23414 
                 ZFPM2 
                 zinc finger protein, 
                 219778_at 
               
               
                   
                   
                   
                   
                 multitype 2 
               
               
                 Stromal-1 
                 NM_080430 
                 140606 
                 SELM 
                 selenoprotein M 
                 226051_at 
               
               
                 Stromal-1 
                 NM_030971 
                 81855 
                 SFXN3 
                 sideroflexin 3 
                 217226_s_at 
               
               
                 Stromal-1 
                 NM_003246 
                 7057 
                 THBS1 
                 thrombospondin 1 
                 201109_s_at 
               
               
                 Stromal-1 
                 NM_003882 
                 8840 
                 WISP1 
                 WNT1 inducible signaling 
                 235821_at 
               
               
                   
                   
                   
                   
                 pathway protein 1 
               
               
                 Stromal-1 
                 NM_005202 
                 1296 
                 COL8A2 
                 collagen, type VIII, alpha 2 
                 221900_at 
               
               
                 Stromal-1 
                 NM_003711 
                 8611 
                 PPAP2A 
                 phosphatidic acid 
                 210946_at 
               
               
                   
                   
                   
                   
                 phosphatase type 2A 
               
               
                 Stromal-1 
                 NM_004995 
                 4323 
                 MMP14 
                 matrix metallopeptidase 
                 202828_s_at 
               
               
                   
                   
                   
                   
                 14 (membrane-inserted) 
               
               
                 Stromal-1 
                 NM_001005336 
                 1759 
                 DNM1 
                 dynamin 1 
                 215116_s_at 
               
               
                 Stromal-1 
                 NM_153717 
                 2121 
                 EVC 
                 Ellis van Creveld 
                 219432_at 
               
               
                   
                   
                   
                   
                 syndrome 
               
               
                 Stromal-1 
                 NM_173462 
                 89932 
                 PAPLN 
                 papilin, proteoglycan-like 
                 226435_at 
               
               
                   
                   
                   
                   
                 sulfated glycoprotein 
               
               
                 Stromal-1 
                 XM_496707 
                 441027 
                 FLJ12993 
                 hypothetical LOC441027 
                 229623_at 
               
               
                 Stromal-1 
                 NM_001839 
                 1266 
                 CNN3 
                 calponin 3, acidic 
                 228297_at 
               
               
                 Stromal-1 
                 NM_015429 
                 25890 
                 ABI3BP 
                 ABI gene family, member 
                 223395_at 
               
               
                   
                   
                   
                   
                 3 (NESH) binding protein 
               
               
                 Stromal-1 
                 NM_002840 
                 5792 
                 PTPRF 
                 protein tyrosine 
                 200636_s_at 
               
               
                   
                   
                   
                   
                 phosphatase, receptor 
               
               
                   
                   
                   
                   
                 type, F 
               
               
                 Stromal-1 
                 NM_001001522 
                 6876 
                 TAGLN 
                 transgelin 
                 1555724_s_at 
               
               
                 Stromal-1 
                 NM_017637 
                 54796 
                 BNC2 
                 basonuclin 2 
                 229942_at 
               
               
                 Stromal-1 
                 NM_003391 
                 7472 
                 WNT2 
                 wingless-type MMTV 
                 205648_at 
               
               
                   
                   
                   
                   
                 integration site family 
               
               
                   
                   
                   
                   
                 member 2 
               
               
                 Stromal-1 
                 NM_015461 
                 25925 
                 ZNF521 
                 zinc finger protein 521 
                 226677_at 
               
               
                 Stromal-1 
                 NM_006475 
                 10631 
                 POSTN 
                 periostin, osteoblast 
                 210809_s_at 
               
               
                   
                   
                   
                   
                 specific factor 
               
               
                 Stromal-1 
                 NM_005418 
                 6764 
                 ST5 
                 suppression of 
                 202440_s_at 
               
               
                   
                   
                   
                   
                 tumorigenicity 5 
               
               
                 Stromal-1 
                 NM_005203 
                 1305 
                 COL13A1 
                 collagen, type XIII, alpha 1 
                 211343_s_at 
               
               
                 Stromal-1 
                 NM_000681 
                 150 
                 ADRA2A 
                 adrenergic, alpha-2A-, 
                 209869_at 
               
               
                   
                   
                   
                   
                 receptor 
               
               
                 Stromal-1 
                 NM_006622 
                 10769 
                 PLK2 
                 polo-like kinase 2 
                 201939_at 
               
               
                   
                   
                   
                   
                 ( Drosophila ) 
               
               
                 Stromal-1 
                 AL528626 
                   
                   
                 Full-length cDNA clone 
                 228573_at 
               
               
                   
                   
                   
                   
                 CS0DD001YA12 of 
               
               
                   
                   
                   
                   
                 Neuroblastoma Cot 50- 
               
               
                   
                   
                   
                   
                 normalized of Homo 
               
               
                   
                   
                   
                   
                 sapiens (human) 
               
               
                 Stromal-1 
                 AF180519 
                 23766 
                 GABARAPL3 
                 GABA(A) receptors 
                 211458_s_at 
               
               
                   
                   
                   
                   
                 associated protein like 3 
               
               
                 Stromal-1 
                 NM_024723 
                 79778 
                 MICALL2 
                 MICAL-like 2 
                 219332_at 
               
               
                 Stromal-1 
                 NM_057177 
                 117583 
                 PARD3B 
                 par-3 partitioning 
                 228411_at 
               
               
                   
                   
                   
                   
                 defective 3 homolog B ( C. elegans ) 
               
               
                 Stromal-1 
                 NM_004949 
                 1824 
                 DSC2 
                 desmocollin 2 
                 226817_at 
               
               
                 Stromal-1 
                 NM_032784 
                 84870 
                 RSPO3 
                 R-spondin 3 homolog 
                 228186_s_at 
               
               
                   
                   
                   
                   
                 ( Xenopus laevis ) 
               
               
                 Stromal-1 
                 NM_007039 
                 11099 
                 PTPN21 
                 protein tyrosine 
                 226380_at 
               
               
                   
                   
                   
                   
                 phosphatase, non- 
               
               
                   
                   
                   
                   
                 receptor type 21 
               
               
                 Stromal-1 
                 NM_031935 
                 83872 
                 HMCN1 
                 hemicentin 1 
                 235944_at 
               
               
                 Stromal-1 
                 AK022877 
                   
                   
                 Clone TUA8 Cri-du-chat 
                 213169_at 
               
               
                   
                   
                   
                   
                 region mRNA 
               
               
                 Stromal-1 
                 AK127644 
                   
                   
                 CDNA FLJ45742 fis, 
                 236297_at 
               
               
                   
                   
                   
                   
                 clone KIDNE2016327 
               
               
                 Stromal-1 
                 AK056963 
                   
                   
                 Full length insert cDNA 
                 226282_at 
               
               
                   
                   
                   
                   
                 clone ZE03F06 
               
               
                 Stromal-1 
                 NM_000899 
                 4254 
                 KITLG 
                 KIT ligand 
                 226534_at 
               
               
                 Stromal-1 
                 NM_002387 
                 4163 
                 MCC 
                 mutated in colorectal 
                 226225_at 
               
               
                   
                   
                   
                   
                 cancers 
               
               
                 Stromal-1 
                 NM_198270 
                 4810 
                 NHS 
                 Nance-Horan syndrome 
                 228933_at 
               
               
                   
                   
                   
                   
                 (congenital cataracts and 
               
               
                   
                   
                   
                   
                 dental anomalies) 
               
               
                 Stromal-1 
                 NM_183376 
                 91947 
                 ARRDC4 
                 arrestin domain 
                 225283_at 
               
               
                   
                   
                   
                   
                 containing 4 
               
               
                 Stromal-1 
                 NM_000216 
                 3730 
                 KAL1 
                 Kallmann syndrome 1 
                 205206_at 
               
               
                   
                   
                   
                   
                 sequence 
               
               
                 Stromal-1 
                 NM_001008224 
                 55075 
                 UACA 
                 uveal autoantigen with 
                 223279_s_at 
               
               
                   
                   
                   
                   
                 coiled-coil domains and 
               
               
                   
                   
                   
                   
                 ankyrin repeats 
               
               
                 Stromal-1 
                 NM_133493 
                 135228 
                 CD109 
                 CD109 molecule 
                 226545_at 
               
               
                 Stromal-1 
                 NM_005545 
                 3671 
                 ISLR 
                 immunoglobulin 
                 207191_s_at 
               
               
                   
                   
                   
                   
                 superfamily containing 
               
               
                   
                   
                   
                   
                 leucine-rich repeat 
               
               
                 Stromal-1 
                 NM_014365 
                 26353 
                 HSPB8 
                 heat shock 22 kDa protein 8 
                 221667_s_at 
               
               
                 Stromal-1 
                 NM_014476 
                 27295 
                 PDLIM3 
                 PDZ and LIM domain 3 
                 209621_s_at 
               
               
                 Stromal-1 
                 NM_020962 
                 57722 
                 NOPE 
                 likely ortholog of mouse 
                 227870_at 
               
               
                   
                   
                   
                   
                 neighbor of Punc E11 
               
               
                 Stromal-1 
                 NM_018357 
                 55323 
                 LARP6 
                 La ribonucleoprotein 
                 218651_s_at 
               
               
                   
                   
                   
                   
                 domain family, member 6 
               
               
                 Stromal-1 
                 NM_012323 
                 23764 
                 MAFF 
                 v-maf 
                 36711_at 
               
               
                   
                   
                   
                   
                 musculoaponeurotic 
               
               
                   
                   
                   
                   
                 fibrosarcoma oncogene 
               
               
                   
                   
                   
                   
                 homolog F (avian) 
               
               
                 Stromal-1 
                 NM_003713 
                 8613 
                 PPAP2B 
                 phosphatidic acid 
                 212230_at 
               
               
                   
                   
                   
                   
                 phosphatase type 2B 
               
               
                 Stromal-1 
                 NM_023016 
                 65124 
                 ANKRD57 
                 ankyrin repeat domain 57 
                 227034_at 
               
               
                 Stromal-1 
                 NM_032777 
                 25960 
                 GPR124 
                 G protein-coupled 
                 65718_at 
               
               
                   
                   
                   
                   
                 receptor 124 
               
               
                 Stromal-1 
                 NM_001554 
                 3491 
                 CYR61 
                 cysteine-rich, angiogenic 
                 201289_at 
               
               
                   
                   
                   
                   
                 inducer, 61 
               
               
                 Stromal-1 
                 NM_145117 
                 89797 
                 NAV2 
                 neuron navigator 2 
                 218330_s_at 
               
               
                 Stromal-1 
                 NM_001002292 
                 79971 
                 GPR177 
                 G protein-coupled 
                 228950_s_at 
               
               
                   
                   
                   
                   
                 receptor 177 
               
               
                 Stromal-1 
                 NM_001401 
                 1902 
                 EDG2 
                 endothelial differentiation, 
                 204036_at 
               
               
                   
                   
                   
                   
                 lysophosphatidic acid G- 
               
               
                   
                   
                   
                   
                 protein-coupled receptor, 2 
               
               
                 Stromal-1 
                 NM_198282 
                 340061 
                 TMEM173 
                 transmembrane protein 
                 224929_at 
               
               
                   
                   
                   
                   
                 173 
               
               
                 Stromal-1 
                 NM_014934 
                 22873 
                 DZIP1 
                 DAZ interacting protein 1 
                 204556_s_at 
               
               
                 Stromal-1 
                 NM_001901 
                 1490 
                 CTGF 
                 connective tissue growth 
                 209101_at 
               
               
                   
                   
                   
                   
                 factor 
               
               
                 Stromal-1 
                 NM_024600 
                 79652 
                 C16orf30 
                 chromosome 16 open 
                 219315_s_at 
               
               
                   
                   
                   
                   
                 reading frame 30 
               
               
                 Stromal-1 
                 NM_138370 
                 91461 
                 LOC91461 
                 hypothetical protein 
                 225380_at 
               
               
                   
                   
                   
                   
                 BC007901 
               
               
                 Stromal-1 
                 NM_014632 
                 9645 
                 MICAL2 
                 microtubule associated 
                 212472_at 
               
               
                   
                   
                   
                   
                 monoxygenase, calponin 
               
               
                   
                   
                   
                   
                 and LIM domain 
               
               
                   
                   
                   
                   
                 containing 2 
               
               
                 Stromal-1 
                 NM_032866 
                 84952 
                 CGNL1 
                 cingulin-like 1 
                 225817_at 
               
               
                 Stromal-1 
                 NM_003687 
                 8572 
                 PDLIM4 
                 PDZ and LIM domain 4 
                 211564_s_at 
               
               
                 Stromal-1 
                 BM544548 
                   
                   
                 Transcribed locus 
                 236179_at 
               
               
                 Stromal-1 
                 NM_001856 
                 1307 
                 COL16A1 
                 collagen, type XVI, alpha 1 
                 204345_at 
               
               
                 Stromal-1 
                 XM_087386 
                 57493 
                 HEG1 
                 HEG homolog 1 
                 213069_at 
               
               
                   
                   
                   
                   
                 (zebrafish) 
               
               
                 Stromal-1 
                 NM_003887 
                 8853 
                 DDEF2 
                 development and 
                 206414_s_at 
               
               
                   
                   
                   
                   
                 differentiation enhancing 
               
               
                   
                   
                   
                   
                 factor 2 
               
               
                 Stromal-1 
                 NM_002844 
                 5796 
                 PTPRK 
                 protein tyrosine 
                 203038_at 
               
               
                   
                   
                   
                   
                 phosphatase, receptor 
               
               
                   
                   
                   
                   
                 type, K 
               
               
                 Stromal-1 
                 NM_022138 
                 64094 
                 SMOC2 
                 SPARC related modular 
                 223235_s_at 
               
               
                   
                   
                   
                   
                 calcium binding 2 
               
               
                 Stromal-1 
                 NM_001006624 
                 10630 
                 PDPN 
                 podoplanin 
                 204879_at 
               
               
                 Stromal-1 
                 NM_003174 
                 6840 
                 SVIL 
                 supervillin 
                 202565_s_at 
               
               
                 Stromal-1 
                 NM_002845 
                 5797 
                 PTPRM 
                 protein tyrosine 
                 1555579_s_at 
               
               
                   
                   
                   
                   
                 phosphatase, receptor 
               
               
                   
                   
                   
                   
                 type, M 
               
               
                 Stromal-1 
                 NM_002889 
                 5919 
                 RARRES2 
                 retinoic acid receptor 
                 209496_at 
               
               
                   
                   
                   
                   
                 responder (tazarotene 
               
               
                   
                   
                   
                   
                 induced) 2 
               
               
                 Stromal-1 
                 NM_006094 
                 10395 
                 DLC1 
                 deleted in liver cancer 1 
                 210762_s_at 
               
               
                 Stromal-1 
                 NM_022463 
                 64359 
                 NXN 
                 nucleoredoxin 
                 219489_s_at 
               
               
                 Stromal-1 
                 AK027294 
                   
                   
                 CDNA FLJ14388 fis, 
                 229802_at 
               
               
                   
                   
                   
                   
                 clone HEMBA1002716 
               
               
                 Stromal-1 
                 NM_005711 
                 10085 
                 EDIL3 
                 EGF-like repeats and 
                 225275_at 
               
               
                   
                   
                   
                   
                 discoidin I-like domains 3 
               
               
                 Stromal-1 
                 NM_000177 
                 2934 
                 GSN 
                 gelsolin (amyloidosis, 
                 200696_s_at 
               
               
                   
                   
                   
                   
                 Finnish type) 
               
               
                 Stromal-1 
                 NM_016639 
                 51330 
                 TNFRSF12A 
                 tumor necrosis factor 
                 218368_s_at 
               
               
                   
                   
                   
                   
                 receptor superfamily, 
               
               
                   
                   
                   
                   
                 member 12A 
               
               
                 Stromal-1 
                 NM_004460 
                 2191 
                 FAP 
                 fibroblast activation 
                 209955_s_at 
               
               
                   
                   
                   
                   
                 protein, alpha 
               
               
                 Stromal-1 
                 NM_000064 
                 718 
                 C3 
                 complement component 3 
                 217767_at 
               
               
                 Stromal-1 
                 NM_016206 
                 389136 
                 VGLL3 
                 vestigial like 3 
                 227399_at 
               
               
                   
                   
                   
                   
                 ( Drosophila ) 
               
               
                 Stromal-1 
                 NM_004339 
                 754 
                 PTTG1IP 
                 pituitary tumor- 
                 200677_at 
               
               
                   
                   
                   
                   
                 transforming 1 interacting 
               
               
                   
                   
                   
                   
                 protein 
               
               
                 Stromal-1 
                 NM_003255 
                 7077 
                 TIMP2 
                 TIMP metallopeptidase 
                 224560_at 
               
               
                   
                   
                   
                   
                 inhibitor 2 
               
               
                 Stromal-1 
                 NM_002998 
                 6383 
                 SDC2 
                 syndecan 2 (heparan 
                 212158_at 
               
               
                   
                   
                   
                   
                 sulfate proteoglycan 1, 
               
               
                   
                   
                   
                   
                 cell surface-associated, 
               
               
                   
                   
                   
                   
                 fibroglycan) 
               
               
                 Stromal-1 
                 NM_012223 
                 4430 
                 MYO1B 
                 myosin IB 
                 212364_at 
               
               
                 Stromal-1 
                 NM_020650 
                 57333 
                 RCN3 
                 reticulocalbin 3, EF-hand 
                 61734_at 
               
               
                   
                   
                   
                   
                 calcium binding domain 
               
               
                 Stromal-1 
                 AL573464 
                   
                   
                 Transcribed locus 
                 229554_at 
               
               
                 Stromal-1 
                 AK001903 
                   
                   
                 CDNA FLJ11041 fis, 
                 227140_at 
               
               
                   
                   
                   
                   
                 clone PLACE1004405 
               
               
                 Stromal-1 
                 NM_005928 
                 4240 
                 MFGE8 
                 milk fat globule-EGF 
                 210605_s_at 
               
               
                   
                   
                   
                   
                 factor 8 protein 
               
               
                 Stromal-1 
                 NM_000943 
                 5480 
                 PPIC 
                 peptidylprolyl isomerase 
                 204518_s_at 
               
               
                   
                   
                   
                   
                 C (cyclophilin C) 
               
               
                 Stromal-1 
                 NM_001008397 
                 493869 
                 LOC493869 
                 similar to RIKEN cDNA 
                 227628_at 
               
               
                   
                   
                   
                   
                 2310016C16 
               
               
                 Stromal-1 
                 AK025431 
                 768211 
                 RELL1 
                 receptor expressed in 
                 226430_at 
               
               
                   
                   
                   
                   
                 lymphoid tissues like 1 
               
               
                 Stromal-1 
                 NM_000297 
                 5311 
                 PKD2 
                 polycystic kidney disease 
                 203688_at 
               
               
                   
                   
                   
                   
                 2 (autosomal dominant) 
               
               
                 Stromal-1 
                 NM_002975 
                 6320 
                 CLEC11A 
                 C-type lectin domain 
                 211709_s_at 
               
               
                   
                   
                   
                   
                 family 11, member A 
               
               
                 Stromal-1 
                 NM_001920 
                 1634 
                 DCN 
                 decorin 
                 211813_x_at 
               
               
                 Stromal-1 
                 NM_001723 
                 667 
                 DST 
                 dystonin 
                 215016_x_at 
               
               
                 Stromal-1 
                 CR749529 
                   
                   
                 MRNA; cDNA 
                 227554_at 
               
               
                   
                   
                   
                   
                 DKFZp686I18116 (from 
               
               
                   
                   
                   
                   
                 clone DKFZp686I18116) 
               
               
                 Stromal-1 
                 NM_000165 
                 2697 
                 GJA1 
                 gap junction protein, 
                 201667_at 
               
               
                   
                   
                   
                   
                 alpha 1, 43 kDa (connexin 
               
               
                   
                   
                   
                   
                 43) 
               
               
                 Stromal-1 
                 NM_012104 
                 23621 
                 BACE1 
                 beta-site APP-cleaving 
                 217904_s_at 
               
               
                   
                   
                   
                   
                 enzyme 1 
               
               
                 Stromal-1 
                 NM_001957 
                 1909 
                 EDNRA 
                 endothelin receptor type A 
                 204464_s_at 
               
               
                 Stromal-1 
                 NM_138455 
                 115908 
                 CTHRC1 
                 collagen triple helix repeat 
                 225681_at 
               
               
                   
                   
                   
                   
                 containing 1 
               
               
                 Stromal-1 
                 NM_001331 
                 1500 
                 CTNND1 
                 catenin (cadherin- 
                 208407_s_at 
               
               
                   
                   
                   
                   
                 associated protein), delta 1 
               
               
                 Stromal-1 
                 NM_001613 
                 59 
                 ACTA2 
                 actin, alpha 2, smooth 
                 200974_at 
               
               
                   
                   
                   
                   
                 muscle, aorta 
               
               
                 Stromal-1 
                 NM_002192 
                 3624 
                 INHBA 
                 inhibin, beta A (activin A, 
                 210511_s_at 
               
               
                   
                   
                   
                   
                 activin AB alpha 
               
               
                   
                   
                   
                   
                 polypeptide) 
               
               
                 Stromal-1 
                 NM_000935 
                 5352 
                 PLOD2 
                 procollagen-lysine, 2- 
                 202620_s_at 
               
               
                   
                   
                   
                   
                 oxoglutarate 5- 
               
               
                   
                   
                   
                   
                 dioxygenase 2 
               
               
                 Stromal-1 
                 NM_015170 
                 23213 
                 SULF1 
                 sulfatase 1 
                 212354_at 
               
               
                 Stromal-1 
                 NM_006039 
                 9902 
                 MRC2 
                 mannose receptor, C type 2 
                 37408_at 
               
               
                 Stromal-1 
                 NM_005261 
                 2669 
                 GEM 
                 GTP binding protein 
                 204472_at 
               
               
                   
                   
                   
                   
                 overexpressed in skeletal 
               
               
                   
                   
                   
                   
                 muscle 
               
               
                 Stromal-1 
                 NM_001008707 
                 2009 
                 EML1 
                 echinoderm microtubule 
                 204797_s_at 
               
               
                   
                   
                   
                   
                 associated protein like 1 
               
               
                 Stromal-1 
                 NM_001031679 
                 253827 
                 MSRB3 
                 methionine sulfoxide 
                 225782_at 
               
               
                   
                   
                   
                   
                 reductase B3 
               
               
                 Stromal-1 
                 NM_001004125 
                 286319 
                 TUSC1 
                 tumor suppressor 
                 227388_at 
               
               
                   
                   
                   
                   
                 candidate 1 
               
               
                 Stromal-1 
                 NM_005965 
                 4638 
                 MYLK 
                 myosin, light chain kinase 
                 202555_s_at 
               
               
                 Stromal-1 
                 NM_016205 
                 56034 
                 PDGFC 
                 platelet derived growth 
                 218718_at 
               
               
                   
                   
                   
                   
                 factor C 
               
               
                 Stromal-1 
                 NM_015976 
                 51375 
                 SNX7 
                 sorting nexin 7 
                 205573_s_at 
               
               
                 Stromal-1 
                 NM_130830 
                 131578 
                 LRRC15 
                 leucine rich repeat 
                 213909_at 
               
               
                   
                   
                   
                   
                 containing 15 
               
               
                 Stromal-1 
                 NM_002026 
                 2335 
                 FN1 
                 fibronectin 1 
                 212464_s_at 
               
               
                 Stromal-1 
                 NM_006855 
                 11015 
                 KDELR3 
                 KDEL (Lys-Asp-Glu-Leu) 
                 204017_at 
               
               
                   
                   
                   
                   
                 endoplasmic reticulum 
               
               
                   
                   
                   
                   
                 protein retention receptor 3 
               
               
                 Stromal-1 
                 NM_002292 
                 3913 
                 LAMB2 
                 laminin, beta 2 (laminin S) 
                 216264_s_at 
               
               
                 Stromal-1 
                 NM_002658 
                 5328 
                 PLAU 
                 plasminogen activator, 
                 205479_s_at 
               
               
                   
                   
                   
                   
                 urokinase 
               
               
                 Stromal-1 
                 NM_005529 
                 3339 
                 HSPG2 
                 heparan sulfate 
                 201655_s_at 
               
               
                   
                   
                   
                   
                 proteoglycan 2 (perlecan) 
               
               
                 Stromal-1 
                 NM_001235 
                 871 
                 SERPINH1 
                 serpin peptidase inhibitor, 
                 207714_s_at 
               
               
                   
                   
                   
                   
                 clade H (heat shock 
               
               
                   
                   
                   
                   
                 protein 47), member 1, 
               
               
                   
                   
                   
                   
                 (collagen binding protein 
               
               
                   
                   
                   
                   
                 1) 
               
               
                 Stromal-1 
                 AJ318805 
                   
                   
                 CDNA FLJ44429 fis, 
                 227061_at 
               
               
                   
                   
                   
                   
                 clone UTERU2015653 
               
               
                 Stromal-1 
                 NM_000396 
                 1513 
                 CTSK 
                 cathepsin K 
                 202450_s_at 
               
               
                 Stromal-1 
                 NM_031302 
                 83468 
                 GLT8D2 
                 glycosyltransferase 8 
                 227070_at 
               
               
                   
                   
                   
                   
                 domain containing 2 
               
               
                 Stromal-1 
                 NM_080821 
                 116151 
                 C20orf108 
                 chromosome 20 open 
                 224690_at 
               
               
                   
                   
                   
                   
                 reading frame 108 
               
               
                 Stromal-1 
                 NM_002345 
                 4060 
                 LUM 
                 lumican 
                 201744_s_at 
               
               
                 Stromal-1 
                 NM_005110 
                 9945 
                 GFPT2 
                 glutamine-fructose-6- 
                 205100_at 
               
               
                   
                   
                   
                   
                 phosphate transaminase 2 
               
               
                 Stromal-1 
                 NM_002941 
                 6091 
                 ROBO1 
                 roundabout, axon 
                 213194_at 
               
               
                   
                   
                   
                   
                 guidance receptor, 
               
               
                   
                   
                   
                   
                 homolog 1 ( Drosophila ) 
               
               
                 Stromal-1 
                 NM_005429 
                 7424 
                 VEGFC 
                 vascular endothelial 
                 209946_at 
               
               
                   
                   
                   
                   
                 growth factor C 
               
               
                 Stromal-1 
                 NM_002213 
                 3693 
                 ITGB5 
                 integrin, beta 5 
                 201125_s_at 
               
               
                 Stromal-1 
                 XM_051017 
                 23363 
                 OBSL1 
                 obscurin-like 1 
                 212775_at 
               
               
                 Stromal-1 
                 NM_181724 
                 338773 
                 TMEM119 
                 transmembrane protein 
                 227300_at 
               
               
                   
                   
                   
                   
                 119 
               
               
                 Stromal-1 
                 NM_003474 
                 8038 
                 ADAM12 
                 ADAM metallopeptidase 
                 213790_at 
               
               
                   
                   
                   
                   
                 domain 12 (meltrin alpha) 
               
               
                 Stromal-1 
                 NM_018222 
                 55742 
                 PARVA 
                 parvin, alpha 
                 217890_s_at 
               
               
                 Stromal-1 
                 NM_006478 
                 10634 
                 GAS2L1 
                 growth arrest-specific 2 
                 31874_at 
               
               
                   
                   
                   
                   
                 like 1 
               
               
                 Stromal-1 
                 NM_000093 
                 1289 
                 COL5A1 
                 collagen, type V, alpha 1 
                 212489_at 
               
               
                 Stromal-1 
                 NM_006288 
                 7070 
                 THY1 
                 Thy-1 cell surface antigen 
                 208851_s_at 
               
               
                 Stromal-1 
                 CD357685 
                   
                 TIMP2 
                 Transcribed locus, 
                 231579_s_at 
               
               
                   
                   
                   
                   
                 strongly similar to 
               
               
                   
                   
                   
                   
                 XP_511714.1 similar to 
               
               
                   
                   
                   
                   
                 Metalloproteinase 
               
               
                   
                   
                   
                   
                 inhibitor 2 precursor 
               
               
                   
                   
                   
                   
                 (TIMP-2) (Tissue inhibitor 
               
               
                   
                   
                   
                   
                 of metalloproteinases-2) 
               
               
                   
                   
                   
                   
                 (CSC-21K) [Pan 
               
               
                   
                   
                   
                   
                 troglodytes] 
               
               
                 Stromal-1 
                 NM_003247 
                 7058 
                 THBS2 
                 thrombospondin 2 
                 203083_at 
               
               
                 Stromal-1 
                 NM_000088 
                 1277 
                 COL1A1 
                 collagen, type I, alpha 1 
                 1556499_s_at 
               
               
                 Stromal-1 
                 NM_006832 
                 10979 
                 PLEKHC1 
                 pleckstrin homology 
                 209210_s_at 
               
               
                   
                   
                   
                   
                 domain containing, family 
               
               
                   
                   
                   
                   
                 C (with FERM domain) 
               
               
                   
                   
                   
                   
                 member 1 
               
               
                 Stromal-1 
                 NM_021961 
                 7003 
                 TEAD1 
                 TEA domain family 
                 224955_at 
               
               
                   
                   
                   
                   
                 member 1 (SV40 
               
               
                   
                   
                   
                   
                 transcriptional enhancer 
               
               
                   
                   
                   
                   
                 factor) 
               
               
                 Stromal-1 
                 AK128814 
                   
                   
                 CDNA FLJ25106 fis, 
                 213675_at 
               
               
                   
                   
                   
                   
                 clone CBR01467 
               
               
                 Stromal-1 
                 NM_153367 
                 219654 
                 C10orf56 
                 chromosome 10 open 
                 212423_at 
               
               
                   
                   
                   
                   
                 reading frame 56 
               
               
                 Stromal-1 
                 AK092048 
                   
                   
                 MRNA; cDNA 
                 227623_at 
               
               
                   
                   
                   
                   
                 DKFZp313C0240 (from 
               
               
                   
                   
                   
                   
                 clone DKFZp313C0240) 
               
               
                 Stromal-1 
                 NM_005245 
                 2195 
                 FAT 
                 FAT tumor suppressor 
                 201579_at 
               
               
                   
                   
                   
                   
                 homolog 1 ( Drosophila ) 
               
               
                 Stromal-1 
                 NM_001129 
                 165 
                 AEBP1 
                 AE binding protein 1 
                 201792_at 
               
               
                 Stromal-1 
                 NM_002403 
                 4237 
                 MFAP2 
                 microfibrillar-associated 
                 203417_at 
               
               
                   
                   
                   
                   
                 protein 2 
               
               
                 Stromal-1 
                 NM_004342 
                 800 
                 CALD1 
                 caldesmon 1 
                 201616_s_at 
               
               
                 Stromal-1 
                 NM_005576 
                 4016 
                 LOXL1 
                 lysyl oxidase-like 1 
                 203570_at 
               
               
                 Stromal-1 
                 NM_199511 
                 151887 
                 CCDC80 
                 coiled-coil domain 
                 225242_s_at 
               
               
                   
                   
                   
                   
                 containing 80 
               
               
                 Stromal-1 
                 NM_012098 
                 23452 
                 ANGPTL2 
                 angiopoietin-like 2 
                 213001_at 
               
               
                 Stromal-1 
                 NM_002210 
                 3685 
                 ITGAV 
                 integrin, alpha V 
                 202351_at 
               
               
                   
                   
                   
                   
                 (vitronectin receptor, 
               
               
                   
                   
                   
                   
                 alpha polypeptide, 
               
               
                   
                   
                   
                   
                 antigen CD51) 
               
               
                 Stromal-1 
                 NM_000366 
                 7168 
                 TPM1 
                 tropomyosin 1 (alpha) 
                 210986_s_at 
               
               
                 Stromal-1 
                 NM_198474 
                 283298 
                 OLFML1 
                 olfactomedin-like 1 
                 217525_at 
               
               
                 Stromal-1 
                 NM_001424 
                 2013 
                 EMP2 
                 epithelial membrane 
                 225078_at 
               
               
                   
                   
                   
                   
                 protein 2 
               
               
                 Stromal-1 
                 NM_032575 
                 84662 
                 GLIS2 
                 GLIS family zinc finger 2 
                 223378_at 
               
               
                 Stromal-1 
                 NM_007173 
                 11098 
                 PRSS23 
                 protease, serine, 23 
                 226279_at 
               
               
                 Stromal-1 
                 NM_001015880 
                 9060 
                 PAPSS2 
                 3′-phosphoadenosine 5′- 
                 203060_s_at 
               
               
                   
                   
                   
                   
                 phosphosulfate synthase 2 
               
               
                 Stromal-1 
                 NM_015645 
                 114902 
                 C1QTNF5 
                 C1q and tumor necrosis 
                 223499_at 
               
               
                   
                   
                   
                   
                 factor related protein 5 
               
               
                 Stromal-1 
                 AK130049 
                   
                   
                 CDNA FLJ26539 fis, 
                 213429_at 
               
               
                   
                   
                   
                   
                 clone KDN09310 
               
               
                 Stromal-1 
                 NM_001849 
                 1292 
                 COL6A2 
                 collagen, type VI, alpha 2 
                 209156_s_at 
               
               
                 Stromal-1 
                 NM_001014796 
                 4921 
                 DDR2 
                 discoidin domain receptor 
                 225442_at 
               
               
                   
                   
                   
                   
                 family, member 2 
               
               
                 Stromal-1 
                 NM_015463 
                 25927 
                 C2orf32 
                 chromosome 2 open 
                 226751_at 
               
               
                   
                   
                   
                   
                 reading frame 32 
               
               
                 Stromal-1 
                 AK055628 
                   
                 ADAM12 
                 CDNA FLJ31066 fis, 
                 226777_at 
               
               
                   
                   
                   
                   
                 clone HSYRA2001153 
               
               
                 Stromal-1 
                 NM_014799 
                 9843 
                 HEPH 
                 hephaestin 
                 203903_s_at 
               
               
                 Stromal-1 
                 NM_004385 
                 1462 
                 CSPG2 
                 chondroitin sulfate 
                 221731_x_at 
               
               
                   
                   
                   
                   
                 proteoglycan 2 (versican) 
               
               
                 Stromal-1 
                 NM_152330 
                 122786 
                 FRMD6 
                 FERM domain containing 6 
                 225481_at 
               
               
                 Stromal-1 
                 BQ917964 
                   
                 PPP4R2 
                 Transcribed locus 
                 235733_at 
               
               
                 Stromal-1 
                 NM_002615 
                 5176 
                 SERPINF1 
                 serpin peptidase inhibitor, 
                 202283_at 
               
               
                   
                   
                   
                   
                 clade F (alpha-2 
               
               
                   
                   
                   
                   
                 antiplasmin, pigment 
               
               
                   
                   
                   
                   
                 epithelium derived factor), 
               
               
                   
                   
                   
                   
                 member 1 
               
               
                 Stromal-1 
                 NM_032348 
                 54587 
                 MXRA8 
                 matrix-remodelling 
                 213422_s_at 
               
               
                   
                   
                   
                   
                 associated 8 
               
               
                 Stromal-1 
                 NM_006106 
                 10413 
                 YAP1 
                 Yes-associated protein 1, 
                 224894_at 
               
               
                   
                   
                   
                   
                 65 kDa 
               
               
                 Stromal-1 
                 NM_020182 
                 56937 
                 TMEPAI 
                 transmembrane, prostate 
                 222449_at 
               
               
                   
                   
                   
                   
                 androgen induced RNA 
               
               
                 Stromal-1 
                 CB999028 
                   
                   
                 Transcribed locus 
                 226834_at 
               
               
                 Stromal-1 
                 NM_001711 
                 633 
                 BGN 
                 biglycan 
                 201261_x_at 
               
               
                 Stromal-1 
                 NM_006902 
                 5396 
                 PRRX1 
                 paired related homeobox 1 
                 226695_at 
               
               
                 Stromal-1 
                 NM_000428 
                 4053 
                 LTBP2 
                 latent transforming growth 
                 204682_at 
               
               
                   
                   
                   
                   
                 factor beta binding protein 2 
               
               
                 Stromal-1 
                 NM_004369 
                 1293 
                 COL6A3 
                 collagen, type VI, alpha 3 
                 201438_at 
               
               
                 Stromal-1 
                 NM_000393 
                 1290 
                 COL5A2 
                 collagen, type V, alpha 2 
                 221730_at 
               
               
                 Stromal-1 
                 NM_015419 
                 25878 
                 MXRA5 
                 matrix-remodelling 
                 209596_at 
               
               
                   
                   
                   
                   
                 associated 5 
               
               
                 Stromal-1 
                 NM_001102 
                 87 
                 ACTN1 
                 actinin, alpha 1 
                 208637_x_at 
               
               
                 Stromal-1 
                 NM_000877 
                 3554 
                 IL1R1 
                 interleukin 1 receptor, 
                 202948_at 
               
               
                   
                   
                   
                   
                 type I 
               
               
                 Stromal-1 
                 NM_015927 
                 7041 
                 TGFB1I1 
                 transforming growth factor 
                 209651_at 
               
               
                   
                   
                   
                   
                 beta 1 induced transcript 1 
               
               
                 Stromal-1 
                 NM_032772 
                 84858 
                 ZNF503 
                 zinc finger protein 503 
                 227195_at 
               
               
                 Stromal-1 
                 NM_020440 
                 5738 
                 PTGFRN 
                 prostaglandin F2 receptor 
                 224937_at 
               
               
                   
                   
                   
                   
                 negative regulator 
               
               
                 Stromal-1 
                 NM_000138 
                 2200 
                 FBN1 
                 fibrillin 1 
                 202765_s_at 
               
               
                 Stromal-1 
                 NM_031442 
                 83604 
                 TMEM47 
                 transmembrane protein 
                 209656_s_at 
               
               
                   
                   
                   
                   
                 47 
               
               
                 Stromal-1 
                 NM_001734 
                 716 
                 C1S 
                 complement component 
                 208747_s_at 
               
               
                   
                   
                   
                   
                 1, s subcomponent 
               
               
                 Stromal-1 
                 NM_002290 
                 3910 
                 LAMA4 
                 laminin, alpha 4 
                 202202_s_at 
               
               
                 Stromal-1 
                 CN312045 
                   
                 PPP4R2 
                 Transcribed locus, weakly 
                 222288_at 
               
               
                   
                   
                   
                   
                 similar to 
               
               
                   
                   
                   
                   
                 NP_001013658.1 protein 
               
               
                   
                   
                   
                   
                 LOC387873 [Homo 
               
               
                   
                   
                   
                   
                 sapiens] 
               
               
                 Stromal-1 
                 NM_000089 
                 1278 
                 COL1A2 
                 collagen, type I, alpha 2 
                 202403_s_at 
               
               
                 Stromal-1 
                 NM_004530 
                 4313 
                 MMP2 
                 matrix metallopeptidase 2 
                 201069_at 
               
               
                   
                   
                   
                   
                 (gelatinase A, 72 kDa 
               
               
                   
                   
                   
                   
                 gelatinase, 72 kDa type IV 
               
               
                   
                   
                   
                   
                 collagenase) 
               
               
                 Stromal-1 
                 NM_001387 
                 1809 
                 DPYSL3 
                 dihydropyrimidinase-like 3 
                 201431_s_at 
               
               
                 Stromal-1 
                 NM_138389 
                 92689 
                 FAM114A1 
                 family with sequence 
                 213455_at 
               
               
                   
                   
                   
                   
                 similarity 114, member A1 
               
               
                 Stromal-1 
                 NM_006670 
                 7162 
                 TPBG 
                 trophoblast glycoprotein 
                 203476_at 
               
               
                 Stromal-1 
                 NM_000304 
                 5376 
                 PMP22 
                 peripheral myelin protein 
                 210139_s_at 
               
               
                   
                   
                   
                   
                 22 
               
               
                 Stromal-1 
                 NM_002775 
                 5654 
                 HTRA1 
                 HtrA serine peptidase 1 
                 201185_at 
               
               
                 Stromal-1 
                 NM_002593 
                 5118 
                 PCOLCE 
                 procollagen C- 
                 202465_at 
               
               
                   
                   
                   
                   
                 endopeptidase enhancer 
               
               
                 Stromal-1 
                 NM_003118 
                 6678 
                 SPARC 
                 secreted protein, acidic, 
                 212667_at 
               
               
                   
                   
                   
                   
                 cysteine-rich 
               
               
                   
                   
                   
                   
                 (osteonectin) 
               
               
                 Stromal-1 
                 NM_007085 
                 11167 
                 FSTL1 
                 follistatin-like 1 
                 208782_at 
               
               
                 Stromal-1 
                 NM_001080393 
                 727936 
                   
                 predicted glycosyl- 
                 235371_at 
               
               
                   
                   
                   
                   
                 transferase 8 domain 
               
               
                   
                   
                   
                   
                 containing 4 
               
               
                 Stromal-1 
                 NM_018153 
                 84168 
                 ANTXR1 
                 anthrax toxin receptor 1 
                 224694_at 
               
               
                 Stromal-1 
                 NM_001733 
                 715 
                 C1R 
                 complement component 
                 212067_s_at 
               
               
                   
                   
                   
                   
                 1, r subcomponent 
               
               
                 Stromal-1 
                 NM_001797 
                 1009 
                 CDH11 
                 cadherin 11, type 2, OB- 
                 207173_x_at 
               
               
                   
                   
                   
                   
                 cadherin (osteoblast) 
               
               
                 Stromal-1 
                 NM_016938 
                 30008 
                 EFEMP2 
                 EGF-containing fibulin- 
                 209356_x_at 
               
               
                   
                   
                   
                   
                 like extracellular matrix 
               
               
                   
                   
                   
                   
                 protein 2 
               
               
                 Stromal-2 
                 NM_014601 
                 30846 
                 EHD2 
                 EH-domain containing 2 
                 45297_at 
               
               
                 Stromal-2 
                 NM_017789 
                 54910 
                 SEMA4C 
                 sema domain, 
                 46665_at 
               
               
                   
                   
                   
                   
                 immunoglobulin domain 
               
               
                   
                   
                   
                   
                 (Ig), transmembrane 
               
               
                   
                   
                   
                   
                 domain (TM) and short 
               
               
                   
                   
                   
                   
                 cytoplasmic domain, 
               
               
                   
                   
                   
                   
                 (semaphorin) 4C 
               
               
                 Stromal-2 
                 NM_000484 
                 351 
                 APP 
                 amyloid beta (A4) 
                 200602_at 
               
               
                   
                   
                   
                   
                 precursor protein 
               
               
                   
                   
                   
                   
                 (peptidase nexin-II, 
               
               
                   
                   
                   
                   
                 Alzheimer disease) 
               
               
                 Stromal-2 
                 NM_004684 
                 8404 
                 SPARCL1 
                 SPARC-like 1 (mast9, 
                 200795_at 
               
               
                   
                   
                   
                   
                 hevin) 
               
               
                 Stromal-2 
                 NM_002291 
                 3912 
                 LAMB1 
                 laminin, beta 1 
                 201505_at 
               
               
                 Stromal-2 
                 NM_000210 
                 3655 
                 ITGA6 
                 integrin, alpha 6 
                 201656_at 
               
               
                 Stromal-2 
                 NM_000552 
                 7450 
                 VWF 
                 von Willebrand factor 
                 202112_at 
               
               
                 Stromal-2 
                 NM_001233 
                 858 
                 CAV2 
                 caveolin 2 
                 203323_at 
               
               
                 Stromal-2 
                 NM_006404 
                 10544 
                 PROCR 
                 protein C receptor, 
                 203650_at 
               
               
                   
                   
                   
                   
                 endothelial (EPCR) 
               
               
                 Stromal-2 
                 NM_000609 
                 6387 
                 CXCL12 
                 chemokine (C—X—C motif) 
                 203666_at 
               
               
                   
                   
                   
                   
                 ligand 12 (stromal cell- 
               
               
                   
                   
                   
                   
                 derived factor 1) 
               
               
                 Stromal-2 
                 NM_002253 
                 3791 
                 KDR 
                 kinase insert domain 
                 203934_at 
               
               
                   
                   
                   
                   
                 receptor (a type III 
               
               
                   
                   
                   
                   
                 receptor tyrosine kinase) 
               
               
                 Stromal-2 
                 NM_001442 
                 2167 
                 FABP4 
                 fatty acid binding protein 
                 203980_at 
               
               
                   
                   
                   
                   
                 4, adipocyte 
               
               
                 Stromal-2 
                 NM_016315 
                 51454 
                 GULP1 
                 GULP, engulfment 
                 204237_at 
               
               
                   
                   
                   
                   
                 adaptor PTB domain 
               
               
                   
                   
                   
                   
                 containing 1 
               
               
                 Stromal-2 
                 NM_006307 
                 8406 
                 SRPX 
                 sushi-repeat-containing 
                 204955_at 
               
               
                   
                   
                   
                   
                 protein, X-linked 
               
               
                 Stromal-2 
                 NM_000163 
                 2690 
                 GHR 
                 growth hormone receptor 
                 205498_at 
               
               
                 Stromal-2 
                 NM_000950 
                 5638 
                 PRRG1 
                 proline rich Gla (G- 
                 205618_at 
               
               
                   
                   
                   
                   
                 carboxyglutamic acid) 1 
               
               
                 Stromal-2 
                 NM_002666 
                 5346 
                 PLIN 
                 perilipin 
                 205913_at 
               
               
                 Stromal-2 
                 NM_000459 
                 7010 
                 TEK 
                 TEK tyrosine kinase, 
                 206702_at 
               
               
                   
                   
                   
                   
                 endothelial (venous 
               
               
                   
                   
                   
                   
                 malformations, multiple 
               
               
                   
                   
                   
                   
                 cutaneous and mucosal) 
               
               
                 Stromal-2 
                 NM_004797 
                 9370 
                 ADIPOQ 
                 adiponectin, C1Q and 
                 207175_at 
               
               
                   
                   
                   
                   
                 collagen domain 
               
               
                   
                   
                   
                   
                 containing 
               
               
                 Stromal-2 
                 NM_000442 
                 5175 
                 PECAM1 
                 platelet/endothelial cell 
                 208981_at 
               
               
                   
                   
                   
                   
                 adhesion molecule (CD31 
               
               
                   
                   
                   
                   
                 antigen) 
               
               
                 Stromal-2 
                 NM_198098 
                 358 
                 AQP1 
                 aquaporin 1 (Colton blood 
                 209047_at 
               
               
                   
                   
                   
                   
                 group) 
               
               
                 Stromal-2 
                 NM_021005 
                 7026 
                 NR2F2 
                 nuclear receptor 
                 209120_at 
               
               
                   
                   
                   
                   
                 subfamily 2, group F, 
               
               
                   
                   
                   
                   
                 member 2 
               
               
                 Stromal-2 
                 NM_014220 
                 4071 
                 TM4SF1 
                 transmembrane 4 L six 
                 209386_at 
               
               
                   
                   
                   
                   
                 family member 1 
               
               
                 Stromal-2 
                 NM_001001549 
                 2887 
                 GRB10 
                 growth factor receptor- 
                 209409_at 
               
               
                   
                   
                   
                   
                 bound protein 10 
               
               
                 Stromal-2 
                 NM_006108 
                 10418 
                 SPON1 
                 spondin 1, extracellular 
                 209436_at 
               
               
                   
                   
                   
                   
                 matrix protein 
               
               
                 Stromal-2 
                 NM_001003679 
                 3953 
                 LEPR 
                 leptin receptor 
                 209894_at 
               
               
                 Stromal-2 
                 NM_000599 
                 3488 
                 IGFBP5 
                 insulin-like growth factor 
                 211959_at 
               
               
                   
                   
                   
                   
                 binding protein 5 
               
               
                 Stromal-2 
                 NM_001753 
                 857 
                 CAV1 
                 caveolin 1, caveolae 
                 212097_at 
               
               
                   
                   
                   
                   
                 protein, 22 kDa 
               
               
                 Stromal-2 
                 NM_005841 
                 10252 
                 SPRY1 
                 sprouty homolog 1, 
                 212558_at 
               
               
                   
                   
                   
                   
                 antagonist of FGF 
               
               
                   
                   
                   
                   
                 signaling ( Drosophila ) 
               
               
                 Stromal-2 
                 NM_015345 
                 23500 
                 DAAM2 
                 dishevelled associated 
                 212793_at 
               
               
                   
                   
                   
                   
                 activator of 
               
               
                   
                   
                   
                   
                 morphogenesis 2 
               
               
                 Stromal-2 
                 NM_015234 
                 221395 
                 GPR116 
                 G protein-coupled 
                 212950_at 
               
               
                   
                   
                   
                   
                 receptor 116 
               
               
                 Stromal-2 
                 NM_006108 
                 10418 
                 SPON1 
                 spondin 1, extracellular 
                 213993_at 
               
               
                   
                   
                   
                   
                 matrix protein 
               
               
                 Stromal-2 
                 NM_016215 
                 51162 
                 EGFL7 
                 EGF-like-domain, multiple 7 
                 218825_at 
               
               
                 Stromal-2 
                 NM_022481 
                 64411 
                 CENTD3 
                 centaurin, delta 3 
                 218950_at 
               
               
                 Stromal-2 
                 XM_371262 
                 64123 
                 ELTD1 
                 EGF, latrophilin and 
                 219134_at 
               
               
                   
                   
                   
                   
                 seven transmembrane 
               
               
                   
                   
                   
                   
                 domain containing 1 
               
               
                 Stromal-2 
                 NM_016563 
                 51285 
                 RASL12 
                 RAS-like, family 12 
                 219167_at 
               
               
                 Stromal-2 
                 NM_006094 
                 10395 
                 DLC1 
                 deleted in liver cancer 1 
                 224822_at 
               
               
                 Stromal-2 
                 NM_019035 
                 54510 
                 PCDH18 
                 protocadherin 18 
                 225975_at 
               
               
                 Stromal-2 
                 NM_019055 
                 54538 
                 ROBO4 
                 roundabout homolog 4, 
                 226028_at 
               
               
                   
                   
                   
                   
                 magic roundabout 
               
               
                   
                   
                   
                   
                 ( Drosophila ) 
               
               
                 Stromal-2 
                 NM_002207 
                 3680 
                 ITGA9 
                 integrin, alpha 9 
                 227297_at 
               
               
                 Stromal-2 
                 XM_930608 
                 641700 
                 ECSM2 
                 endothelial cell-specific 
                 227779_at 
               
               
                   
                   
                   
                   
                 molecule 2 
               
               
                 Stromal-2 
                 XM_037493 
                 85358 
                 SHANK3 
                 SH3 and multiple ankyrin 
                 227923_at 
               
               
                   
                   
                   
                   
                 repeat domains 3 
               
               
                 Stromal-2 
                 NM_052954 
                 116159 
                 CYYR1 
                 cysteine/tyrosine-rich 1 
                 228665_at 
               
               
                 Stromal-2 
                 NM_002837 
                 5787 
                 PTPRB 
                 protein tyrosine 
                 230250_at 
               
               
                   
                   
                   
                   
                 phosphatase, receptor 
               
               
                   
                   
                   
                   
                 type, B 
               
               
                 Stromal-2 
                 NM_019558 
                 3234 
                 HOXD8 
                 homeobox D8 
                 231906_at 
               
               
                 Stromal-2 
                 NM_001442 
                 2167 
                 FABP4 
                 fatty acid binding protein 
                 235978_at 
               
               
                   
                   
                   
                   
                 4, adipocyte 
               
               
                 Stromal-2 
                 NM_024756 
                 79812 
                 MMRN2 
                 multimerin 2 
                 236262_at 
               
               
                 Stromal-2 
                 BQ897248 
                   
                   
                 Transcribed locus 
                 242680_at 
               
               
                 Stromal-2 
                 NM_020663 
                 57381 
                 RHOJ 
                 ras homolog gene family, 
                 243481_at 
               
               
                   
                   
                   
                   
                 member J 
               
               
                 Stromal-2 
                 AK091419 
                   
                   
                 CDNA FLJ34100 fis, 
                 1558397_at 
               
               
                   
                   
                   
                   
                 clone FCBBF3007597 
               
               
                 Stromal-2 
                 NM_015719 
                 50509 
                 COL5A3 
                 collagen, type V, alpha 3 
                 52255_s_at 
               
               
                 Stromal-2 
                 NM_012072 
                 22918 
                 CD93 
                 CD93 molecule 
                 202878_s_at 
               
               
                 Stromal-2 
                 NM_000300 
                 5320 
                 PLA2G2A 
                 phospholipase A2, group 
                 203649_s_at 
               
               
                   
                   
                   
                   
                 IIA (platelets, synovial 
               
               
                   
                   
                   
                   
                 fluid) 
               
               
                 Stromal-2 
                 NM_019105 
                 7148 
                 TNXB 
                 tenascin XB 
                 206093_x_at 
               
               
                 Stromal-2 
                 NM_030754 
                 6289 
                 SAA2 
                 serum amyloid A2 
                 208607_s_at 
               
               
                 Stromal-2 
                 NM_019105 
                 7148 
                 TNXB 
                 tenascin XB 
                 208609_s_at 
               
               
                 Stromal-2 
                 NM_014220 
                 4071 
                 TM4SF1 
                 transmembrane 4 L six 
                 209387_s_at 
               
               
                   
                   
                   
                   
                 family member 1 
               
               
                 Stromal-2 
                 NM_000668 
                 125 
                 ADH1B 
                 alcohol dehydrogenase IB 
                 209612_s_at 
               
               
                   
                   
                   
                   
                 (class I), beta polypeptide 
               
               
                 Stromal-2 
                 NM_000668 
                 125 
                 ADH1B 
                 alcohol dehydrogenase IB 
                 209613_s_at 
               
               
                   
                   
                   
                   
                 (class I), beta polypeptide 
               
               
                 Stromal-2 
                 NM_001354 
                 1646 
                 AKR1C2 
                 aldo-keto reductase 
                 209699_x_at 
               
               
                   
                   
                   
                   
                 family 1, member C2 
               
               
                   
                   
                   
                   
                 (dihydrodiol 
               
               
                   
                   
                   
                   
                 dehydrogenase 2; bile 
               
               
                   
                   
                   
                   
                 acid binding protein; 3- 
               
               
                   
                   
                   
                   
                 alpha hydroxysteroid 
               
               
                   
                   
                   
                   
                 dehydrogenase, type III) 
               
               
                 Stromal-2 
                 NM_001032281 
                 7035 
                 TFPI 
                 tissue factor pathway 
                 210664_s_at 
               
               
                   
                   
                   
                   
                 inhibitor (lipoprotein- 
               
               
                   
                   
                   
                   
                 associated coagulation 
               
               
                   
                   
                   
                   
                 inhibitor) 
               
               
                 Stromal-2 
                 NM_001001924 
                 57509 
                 MTUS1 
                 mitochondrial tumor 
                 212096_s_at 
               
               
                   
                   
                   
                   
                 suppressor 1 
               
               
                 Stromal-2 
                 NM_019105 
                 7148 
                 TNXB 
                 tenascin XB 
                 213451_x_at 
               
               
                 Stromal-2 
                 NM_004449 
                 2078 
                 ERG 
                 v-ets erythroblastosis 
                 213541_s_at 
               
               
                   
                   
                   
                   
                 virus E26 oncogene 
               
               
                   
                   
                   
                   
                 homolog (avian) 
               
               
                 Stromal-2 
                 NM_018407 
                 55353 
                 LAPTM4B 
                 lysosomal associated 
                 214039_s_at 
               
               
                   
                   
                   
                   
                 protein transmembrane 4 
               
               
                   
                   
                   
                   
                 beta 
               
               
                 Stromal-2 
                 NM_000331 
                 6288 
                 SAA1 
                 serum amyloid A1 
                 214456_x_at 
               
               
                 Stromal-2 
                 NM_019105 
                 7148 
                 TNXB 
                 tenascin XB 
                 216333_x_at 
               
               
                 Stromal-2 
                 NM_001034954 
                 10580 
                 SORBS1 
                 sorbin and SH3 domain 
                 218087_s_at 
               
               
                   
                   
                   
                   
                 containing 1 
               
               
                 Stromal-2 
                 NM_017734 
                 54873 
                 PALMD 
                 palmdelphin 
                 218736_s_at 
               
               
                 Stromal-2 
                 NM_024756 
                 79812 
                 MMRN2 
                 multimerin 2 
                 219091_s_at 
               
               
                 Stromal-2 
                 NM_006744 
                 5950 
                 RBP4 
                 retinol binding protein 4, 
                 219140_s_at 
               
               
                   
                   
                   
                   
                 plasma 
               
               
                 Stromal-2 
                 NM_001034954 
                 10580 
                 SORBS1 
                 sorbin and SH3 domain 
                 222513_s_at 
               
               
                   
                   
                   
                   
                 containing 1 
               
               
                   
               
            
           
         
       
     
     The DLBCL survival predictors of the invention were generated using expression data and methods described in Examples 1 and 2, below. The first bivariate survival predictor incorporates the GCB and stromal-1 gene expression signatures. Fitting the Cox proportional hazards model to the gene expression data obtained from these two signatures resulted in a bivariate model survival predictor score calculated using the following generalized equation:
 
Bivariate DLBCL survival predictor score= A −[( x )*( GCB  signature value)]−[( y )*(stromal-1 signature value)].
 
In this equation, A is an offset term, while (x) and (y) are scale factors. The GCB signature value and the stromal-1 signature value can correspond to the average of the expression levels of all genes in the GCB signature and the stromal-1 signature, respectively. A lower survival predictor score indicates a more favorable survival outcome, and a higher survival predictor score indicates a less favorable survival outcome for the subject.
 
     The bivariate survival predictor was refined into a multivariate survival predictor that incorporates GCB, stromal-1, and stomal-2 gene expression signatures. Fitting the Cox proportional hazards model to the gene expression data obtained from these three signatures resulted in a multivariate model survival predictor score calculated using the following generalized equation:
 
General multivariate DLBCL survival predictor score= A −[( x )*( GCB  signature value)]−[( y )*(stromal-1 signature value)]+[( z )*(stromal-2 signature value)].
 
In this equation, A is an offset term, while (x), (y), and (z) are scale factors. The GCB signature value, the stromal-1 signature value, and the stromal-2 signature value can correspond to the average of the expression levels of all genes in the GCB signature, the stromal-1 signature, and the stromal-2 signature, respectively. A lower survival predictor score indicates a more favorable survival outcome and a higher survival predictor score indicates a less favorable survival outcome for the subject.
 
     In one embodiment, the invention provides the following multivariate survival predictor equation:
 
Multivariate DLBCL survival predictor score=8.11−[0.419*( GCB  signature value)]−[1.015*(stromal-1 signature value)]+[0.675*(stromal-2 signature value)]
 
In this equation, a lower survival predictor score indicates a more favorable survival outcome, and a higher survival predictor score indicates a poorer survival outcome for the subject.
 
     In other embodiments of the multivariate DLBCL survival predictor score equation, the offset term (A) or (8.11) can be varied without affecting the equation&#39;s usefulness in predicting clinical outcome. Scale factors (x), (y), and (z) can also be varied, individually or in combination. For example, scale factor (x) can be from about 0.200 or more, from about 0.225 or more, from about 0.250 or more, from about 0.275 or more, from about 0.300, from about 0.325 or more, from about 0.350 or more, from about 0.375 or more, or from about 0.400 or more. Alternatively, or in addition, scale factor (x) can be about 0.625 or less, about 0.600 or less, about 0.575 or less, about 0.550 or less, about 0.525 or less, about 0.500 or less, about 0.475 or less, about 0.450 or less, or about 0.425 or less. Thus, scale factor (z) can be one that is bounded by any two of the previous endpoints. For example scale factor (x) can be a value from 0.200-0.625, from 0.350-0.550, from 0.350-0.475, or from 0.400-0.425. Similarly, scale factor (y) can be from about 0.800 or more, from about 0.825 or more, from about 0.850 or more, from about 0.875 or more, from about 0.900 or more, from about 0.925 or more, from about 0.950 or more, from about 0.975 or more, or from about 1.000 or more. Alternatively, or in addition, scale factor (y) can be, e.g., about 1.250 or less, e.g., about 1.225 or less, about 1.200, about 1.175 or less, about 1.150 or less, about 1.125 or less, about 1.100 or less, about 1.075 or less, about 1.050 or less, or about 1.025 or less. Thus, scale factor (y) can be one that is bounded by any two of the previous endpoints. For example, scale factor (y) can be a value from 0.800-1.250, a value from 0.950-1.1025, a value from 0.950-1.200 or a value from 1.000-1.025. Also similarly, scale factor (z) can be from about 0.450 or more, about 0.475 or more, about 0.500 or more, about 0.525 or more, about 0.550 or more, about 0.575 or more, about 0.600 or more, about 0.625 or more, or about 0.650 or more. Alternatively, or in addition, scale factor (z) can be, e.g., about 0.900 or less, e.g., about 0.875 or less, about 0.850, about 0.825 or less, about 0.800 or less, about 0.775 or less, about 0.750 or less, or about 0.725 or less. Thus, scale factor (z) can be one that is bounded by any two of the previous endpoints. For example, scale factor (z) can be a value from 0.450-0.900, any value from 0.650-0.725, any value from 0.625-0.775 or any value from 0.650-0.700. 
     Furthermore, the invention includes any set of scale factors (x), (y), and (z) in conjunction in the general multivariate DLBCL survival predictor score that creates a function that is monotonically related to a multivariate DLBCL survival predictor score equation using any combination of the foregoing specified scale factor (x), (y), and (z) values. 
     In some embodiments of the invention, a survival predictor score can be calculated using fewer than all of the gene components of the GCB signature, the stromal-1 signature, and/or the stromal-2 signature listed in Table 1. For example, the survival prediction equations disclosed herein can be calculated using mathematical combinations of the expressions of 98% (38), 95% (37), 93% (36), or 90% (35) of the genes listed in Table 1 for the GCB signature, about 99% (about 280), about 98% (about 277), 97% (about 275), about 96% (about 272), about 95% (about 270), about 94% (about 266), about 93% (about 263), about 92% (about 260), about 91% (about 257), or about 90% (about 255) of the genes listed in Table 1 for the stromal-1 signature, and/or 99% (71), 97% (70), 96% (69), 95% (68) 93% (67), 92% (66), or 90% (65) of the genes listed in Table 1 for the stromal-2 signature (instead of using all of the genes corresponding to a gene signature in Table 1 to calculate the GCB signature value, the stromal-1 signature value, and/or stromal-2 signature value, respectively). In other embodiments, the survival prediction equations disclosed herein can be calculated using mathematical combinations of the expressions of 88% (34 genes), 85% (33 genes), 82% (32 genes), 80% (31 genes) of the genes listed in Table 1 for the GCB signature, about 89% (about 252), about 88% (about 249), about 87% (about 246), about 86% (about 243), about 85% (about 241), about 84% (about 238), about 83% (about 235), about 82% (about 232), about 81% (about 229), or about 80% (about 226) of the genes listed in Table 1 for the stromal-1 signature, and/or 89% (64), 88% (63), 86% (62), 85% (61), 83% (60), 82% (59) or 80% (58) of the genes listed in Table 1 for the stromal-2 signature (instead of using all of the genes corresponding to a gene signature in Table 1 to calculate the GCB signature value, the stromal-1 signature value, and/or stromal-2 signature value, respectively). 
     The invention also provides a method of using a DLBCL survival predictor score to predict the probability of a survival outcome beyond an amount of time t following treatment for DLBCL. The method includes calculating the probability of a survival outcome for a subject using the following general equation:
 
 P ( SO )= SO   0 ( t ) (exp((s)*(survival predictor score)))  
 
In this equation, P(SO) is the subject&#39;s probability of the survival outcome beyond time t following treatment for DLBCL, SO 0 (t) is the probability of survival outcome, which corresponds to the largest time value smaller than t in a survival outcome curve, and (s) is a scale factor. Treatment for DLBCL can include chemotherapy and the administration of Rituximab. A survival curve can be calculated using statistical methods, such as the Cox Proportional Hazard Model. Additional information regarding survival outcome curves is set forth in Lawless,  Statistical Models and Methods for Lifetime Data , John Wiley and Sons (New York 1982) and Kalbfleisch et al.,  Biometrika,  60: 267-79 (1973).
 
     In one embodiment, the method of the invention includes calculating the probability of overall survival for a subject beyond an amount of time t following treatment for DLBCL. The method includes calculating the probability of a survival outcome for a subject using the following general equation:
 
 P ( OS )= SO   0 ( t ) (exp(survival predictor score))  
 
In the equation, P(OS) is the subject&#39;s probability of overall survival beyond time t following treatment for DLBCL, SO 0 (t) is the curve probability of survival outcome, which corresponds to the largest time value in a survival curve which is smaller than t, and the general equation scale factor (s)=1. Treatment for DLBCL can include chemotherapy alone or in combination with the administration of Rituximab (R-CHOP).
 
     In another embodiment, the method of the invention includes calculating the probability of progression-free survival for a subject beyond an amount of time t following treatment for DLBCL. The method includes calculating the probability of a survival outcome for a subject using the following general equation:
 
 P ( PFS )= SO   0 ( t ) (exp(0.976*(survival predictor score)))  
 
In this equation, P(PFS) is the subject&#39;s probability of progression-free survival beyond time t following treatment for DLBCL, SO 0 (t) is the curve probability of progression-free survival, which corresponds to the largest time value in a survival curve which is smaller than t, and the general equation scale factor (s)=0.976. The treatment for DLBCL can include chemotherapy alone or in combination with the administration of Rituximab (R-CHOP).
 
     The foregoing equations for P(OS) and P(PFS) were generated by maximizing the partial likelihoods of the Cox proportional hazards model within the LLMPP CHOP data described below in Examples 1 and 2. Separate single variable Cox proportional hazards models were considered for overall survival P(OS) and for progression free survival P(PFS) based on this model score formulation. The single variable scale factor (1.0 for overall survival and 0.997 for progression free survival) were generated for each model by maximization of the partial likelihoods within the R-CHOP patients described below in Examples 1 and 2. 
     In other embodiments, the scale factor in the foregoing P(PFS) can be varied such that (instead of 0.976) scale factor (s) is a value between 0.970 and 0.980, e.g. 0.971, 0.972, 0.973, 0.973, 0.974, 0.975, 0.977, 0.978, and 0.979. 
     The invention also provides a method of selecting a subject for antiangiogenic therapy of DLBCL based on the subject&#39;s high relative expression of stromal-2 signature genes. As discussed more fully below in Example 4, the stromal-2 signature includes a number of genes whose expression or gene products are related to angiogenesis. Thus, high relative expression of stromal-2 signature genes in DLBCL can be indicative of high angiogenic activity. Moreover, high relative expression of stromal-2 signature genes can be related to the heavy infiltration of some DLBCL tumors with myeloid lineage cells. Accordingly, subjects with high relative expression of stromal-2 signature genes are good candidates for treatment with antiangiogenic therapy, either alone or in combination with other anti-oncogenic therapies. Furthermore, as also discussed more fully in Example 4, a stromal score, which was obtained by subtracting the stromal-1 signature value from the stromal-2 signature value, was observed to correlate with high tumor blood vessel density. 
     In this regard, the antiangiogenic monoclonal antibody to vascular endothelial growth factor bevacizumab has been clinically tested in patients with DLBCL (Ganjoo et al.,  Leuk. Lymphoma,  47: 998-1005 (2006)). Other antiangiogenic therapies can include small molecule inhibitors of SDF-1 receptor, such as CXCR4 (Petit et al.,  Trends Immunol.,  28: 299-307 (2007). Still another example of an antiangiogenic therapy can include blocking antibodies to the myeloid lineage cell marker CTGF, which has been implicated in angiogenesis. Moreover, anti-CTGF antibodies have been shown to have anti-cancer activity in pre-clinical models of cancer (Aikawa et al.,  Mol. Cancer Ther.,  5: 1108-16 (2006)). 
     In one embodiment, the method of the invention for selecting a subject for antiangiogenic therapy includes obtaining a gene expression profile from a DLBCL biopsy from the subject. The subject&#39;s stromal-2 signature value is determined. The subject&#39;s stromal-2 signature value is then compared to a standard stromal-2 value. A standard stromal-2 value corresponds to the average of multiple stromal-2 signature values in DLBCL biopsy samples from a plurality of randomly selected subjects with DLBCL, e.g., more than 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, or 250 randomly selected subjects with DLBCL. If the subject&#39;s stromal-2 signature value is significantly higher than the standard stromal-2 value, then the subject can be treated with anti-angiogenic therapy. 
     In another embodiment, the method of the invention for selecting a subject for anti-angiogenic therapy includes obtaining a gene expression profile from a DLBCL biopsy from the subject. The subject&#39;s stromal 1 signature value and stromal-2 signature value are determined. The stromal-1 signature value is then subtracted from the stromal-2 signature value to obtain a stomal score. The subject&#39;s stromal score is then compared to a standard stromal score. A standard stromal score corresponds to the average of multiple stromal scores (each stromal score=[stromal-2 signature value])−[stromal-1 signature value]) derived from DLBCL biopsy samples from a plurality of randomly selected subjects with DLBCL, e.g., more than 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, or 250 randomly selected subjects with DLBCL. If the subject&#39;s stromal score is significantly higher than the standard stromal score, then the subject can be treated with anti-angiogenic therapy. 
     The invention further provides a targeted array that can be used to detect the expression levels of all or most of the genes in a germinal center B cell gene (GCB) expression signature, a stromal-1 gene expression signature, and/or a stromal-2 gene expression signature. A targeted array, as used herein, is an array directed to a limited set of genes and thus differs from a whole genome array. The targeted array of the invention can include probes for fewer than 20,000 genes, fewer than 15,000 genes, fewer than 10,000 genes, fewer than 8,000 genes, fewer than 7,000 genes, fewer than 6,000 genes, fewer than 5,000 genes, or fewer than 4,000 genes. Generally, the targeted array includes probes for at least 80% of the genes in a germinal center B cell gene (GCB) expression signature, a stromal-1 gene expression signature, and/or a stromal-2 gene expression signature. The targeted arrays of the invention can be used, for example, to detect expression levels for use in the methods described herein. 
     The invention provides a targeted array that includes probes for all of the genes in the stromal-1 gene expression signature. The invention also provides a targeted array that includes probes for all of the genes in the stromal-2 gene expression signature. Additionally, the invention provides a targeted array that includes probes for all of the genes in the stromal-1 gene expression signature and all of the genes in the stromal-2 gene expression signature. Moreover, the invention provides a targeted array that includes probes for all of the genes in the stromal-1 gene expression signature, all of the genes in the stromal-2 gene expression signature, and all of the genes in the GCB signature. 
     In certain embodiments, the arrays of the invention can include 98% (38), 95% (37), 93% (36), or 90% (35) of the genes listed in Table 1 for the GCB signature, about 99% (about 280), about 98% (about 277), 97% (about 275), about 96% (about 272), about 95% (about 270), about 94% (about 266), about 93% (about 263), about 92% (about 260), about 91% (about 257), or about 90% (about 255) of the genes listed in Table 1 for the stromal-1 signature, and/or 99% (71), 97% (70), 96% (69), 95% (68) 93% (67), 92% (66), or 90% (65) of the genes listed in Table 1 for the stromal-2 signature (instead of all of the genes listed in Table 1 for the GCB signature average, the stromal-1 signature average, and/or stromal-2 signature average, respectively). In certain embodiments, the arrays of the invention can include 88% (34 genes), 85% (33 genes), 82% (32 genes), 80% (31 genes) of the genes listed in Table 1 for the GCB signature, about 89% (about 252), about 88% (about 249), about 87% (about 246), about 86% (about 243), about 85% (about 241), about 84% (about 238), about 83% (about 235), about 82% (about 232), about 81% (about 229), or about 80% (about 226) of the genes listed in Table 1 for the stromal-1 signature, and/or 89% (64), 88% (63), 86% (62), 85% (61), 83% (60), 82% (59) or 80% (58) of the genes listed in Table 1 for the stromal-2 signature (instead of all of the genes listed in Table 1 for the GCB signature average, the stromal-1 signature average, and/or stromal-2 signature average, respectively). 
     The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. 
     Example 1 
     This example demonstrates that significant differences were found between the survival outcomes for R-CHOP treated ABC DLBCL and GCB DLBCL patients and that survival outcome correlated with three prognostic gene expression signatures. 
     Pre-treatment tumor biopsy specimens and clinical data were obtained from 414 patients with de novo DLBCL treated at 10 institutions in North America and Europe and studied according to a protocol approved by the National Cancer Institute&#39;s Institutional Review Board. Patients included in a “LLMP CHOP cohort” of 181 patients were treated with anthracycline-based combinations, most often cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or similar regimens, as previously described (Rosenwald et al.,  N. Engl. J. Med.,  346: 1937-47 (2002)). The remaining 233 patients constituted an R-CHOP cohort that received similar chemotherapy plus Rituximab. The median follow-up in the R-CHOP cohort was 2.1 years (2.8 years for survivors). A panel of expert hematopathologists confirmed the diagnosis of DLBCL using current WHO criteria. Additional clinical patient characteristics for the R-CHOP cohort are described in Table 2. Additional analysis used a second “MMMNLP CHOP” cohort of 177 patients studied by the Molecular Mechanisms of Non-Hodgkin&#39;s Lymphoma Network Project (Hummel et al.,  N. Engl. J. Med.,  354: 2419-30 (2006)). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Clinical characteristics of DLBCL patients treated with R-CHOP 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 % Germinal 
                 % Activated 
                 % 
                   
               
               
                   
                 % 
                 center B cell- 
                 B cell-like 
                 Unclassified 
               
               
                   
                 Total 
                 like DLBCL 
                 DLBCL 
                 DLBCL 
               
               
                 Characteristic 
                 (N = 233) 
                 (N = 107) 
                 (N = 93) 
                 (N = 33) 
                 P-value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Age &gt;60 yr 
                 52 
                 47 
                 63 
                 39 
                 0.02 
               
               
                 Ann Arbor stage &gt; II 
                 54 
                 48 
                 62 
                 50 
                 0.06 
               
               
                 Lactate 
                 48 
                 43 
                 58 
                 41 
                 0.06 
               
               
                 Dehydrogenase &gt;1x 
               
               
                 Normal 
               
               
                 No. of extranodal 
                 15 
                 14 
                 15 
                 14 
                 0.8 
               
               
                 sites &gt;1 
               
               
                 Eastern Cooperative 
                 25 
                 17 
                 33 
                 27 
                 0.02 
               
               
                 Oncology Group 
               
               
                 (ECOG) performance 
               
               
                 status 
               
               
                 International 
                   
                   
                   
                   
                 &lt;0.001 
               
               
                 Prognostic Index 
               
               
                 (IPI) Score 
               
               
                 0 or 1 
                 41 
                 55 
                 21 
                 50 
               
               
                 2 or 3 
                 46 
                 33 
                 63 
                 38 
               
               
                 4 or 5 
                 13 
                 12 
                 15 
                 12 
               
               
                 Revised IPI Score 
                   
                   
                   
                   
                 &lt;0.001 
               
               
                 0 
                 19 
                 27 
                 5 
                 28 
               
               
                 1 or 2 
                 56 
                 52 
                 64 
                 48 
               
               
                 3-5 
                 25 
                 21 
                 31 
                 24 
               
               
                   
               
            
           
         
       
     
     Gene expression profiling was performed using Affymetrix U133+2.0 microarrays. Gene expression profiling data are available through the National Center for Biotechnology Information web site as described in Lenz et al.,  New Engl. J. Med.  359: 2313-23 (2008), at page 2314. All gene expression array data were normalized using MAS 5.0 software, and were log 2 transformed. To account for technical differences in the microarray processing between the R-CHOP cohort data and the LLMPP CHOP cohort data, the expression values of each gene in the R-CHOP cohort data were adjusted so that its median matched the median of the LLMPP CHOP data. 
     Gene expression signature identification and survival predictor model development were based solely on the data from the LLMPP CHOP training set. No prior survival analysis or subgroup analysis was performed with the test sets (MMMLNP CHOP and R-CHOP cohorts). The Cox model was used to identify genes associated with survival in the CHOP training set and to build multivariate survival models. The models and their associated scaling coefficients were fixed based on the CHOP training set and then evaluated on the test sets. The P-values of survival effects of continuous variables such as gene expression or signature expression were calculated with the Cox likelihood ratio test. The significance of survival effects based on discrete variables such as lymphoma subtype or International Prognostic Index (IPI) was calculated using the log rank test. Validation P-values presented are one-sided in the direction observed in the training set. All other P-values were two sided. Survival curves were estimated using the Kaplan-Meier method. 
     All aspects of gene expression signature identification and survival predictor model development were based solely on the data from the CHOP training set. No prior survival analysis or subgroup analysis was performed with the test sets (MMMLNP CHOP and R-CHOP cohorts). The Cox model was used to identify genes associated with survival in the CHOP training set and to build multivariate survival models. The models and their associated scale factors were fixed based on the CHOP training set, and then evaluated on the test sets. 
     Since ABC and GCB DLBCL subtypes have distinct overall survival rates with CHOP chemotherapy (Rosenwald et al.,  N. Engl. J. Med.,  346: 1937-47 (2002); Alizadeh et al.,  Nature,  403:503-11(2000); Hummel et al.,  N. Engl. J. Med.,  354:2419-30 (2006);  Monti, Blood,  105:1851-61(2005)), whether this distinction remains prognostically significant among patients treated with R-CHOP was tested (Coiffier et al,  N. Engl. J. Med.,  346: 235-42 (2002)). Gene expression profiles were determined for pre-treatment biopsy samples from a “training set” of 181 patients treated with CHOP or CHOP-like chemotherapy alone and from a “test set” of 233 patients treated with R-CHOP. The patients in these two cohorts were comparable with respect to age range and distribution of the clinical prognostic variables that constitute the International Prognostic Index (IPI) (Table 2). In the R-CHOP cohort, patients with GCB DLBCL had better survival rates than those with ABC DLBCL. Specifically, R-CHOP treated GCB DLBCL and ABC DLBCL patients had 3-year overall survival rates of 84% and 56%, respectively, and 3-year progression-free survival rates of 74% and 40%, respectively ( FIGS. 1A and 1B ). In the CHOP training set, and in a second “MMMLMP” CHOP cohort (Hummel et al., supra), the overall survival rates for ABC DLBCL and GCB DLBCL were lower than in the R-CHOP cohort ( FIG. 6 ). Multivariate analysis indicated that the relative benefit (i.e., change in survival outcome) due to R-CHOP therapy (as compared to CHOP) was not significantly different between ABC and GCB DLBCL. 
     Four gene expression signatures have been previously shown to have prognostic significance in DLBCL patients treated with CHOP (Rosenwald et al., supra). Of these, the GCB signature and lymph node signature were associated with favorable survival, and the proliferation signature was associated with inferior survival within the CHOP training set, in the MMMLNP CHOP cohort (see the corresponding signature panels in  FIG. 7 ), and in the R-CHOP cohort (see corresponding signature panels in  FIG. 1C ). Thus, the biological differences among DLBCL tumors reflected by these three signatures remain prognostically important in Rituximab treated patients, even though Rituximab treatment generally improved survival in DLBCL. 
     The remaining fourth gene expression signature, the MHC class II signature, which was associated with survival in the CHOP training set when treated as a continuous variable, was not associated with survival in the R-CHOP cohort (see MHC class II signature panel in  FIG. 1C ). Moreover, tumors with extremely low “outlier” expression of this signature were associated with inferior survival in both CHOP cohorts (see  FIGS. 8A and 8B ), but not in the R-CHOP cohort (see  FIG. 8C ). 
     The foregoing results indicate that Rituximab immunotherapy combined with chemotherapy (R-CHOP) benefits both the ABC and GCB subtypes of DLBCL and that gene expression signatures that predicted survival in the context of CHOP chemotherapy retained their prognostic power among R-CHOP-treated patients. 
     The foregoing results also indicate that the biological variation among DLBCL tumors, as measured by gene expression signatures, has a consistent relationship to therapeutic response regardless of the treatment regimen used. There is a striking difference in 3-year progression-free survival between ABC DLBCL patients and GCB DLBCL patients treated with R-CHOP (40% vs. 74%). This difference is likely due to genetic and biological differences between these DLBCL subtypes (Staudt et al.,  Adv. Immunol.,  87: 163-208 (2005)). 
     Hence, future clinical trials in DLBCL should incorporate quantitative methods to discern these biological differences so that patient cohorts in different trials can be compared and treatment responses can be related to defined tumor phenotypes. 
     Example 2 
     This example demonstrates the development of GCB, stromal-1, and stromal-2 survival signatures and a related multivariate model of survival for R-CHOP-treated DLBCL. 
     Unless otherwise indicated, patient cohorts and methods of gene expression analysis are as described in Example 1. 
     In the LLMPP CHOP cohort data, 936 genes were identified as associated with poor prognosis p&lt;0.01 (1-sided). For genes having multiple array probe sets associated with survival, only the probe set with the strongest association with survival was used. The expression values of the probe sets in the LLMPP CHOP cohort data were then clustered. The largest cluster with an average correlation of &gt;0.6 and containing myc was identified as the proliferation survival signature. 1396 genes were identified as associated with favorable outcome. The largest cluster with average correlation of &gt;0.6 and containing BCL6 was identified as the germinal center B cell (GCB) survival signature. A cluster with average correlation of &gt;0.6 and containing FN1 was identified as the stromal-1 survival signature, whereas another cluster with average correlation of &gt;0.6 containing HLADRA was identified as the MHC class II survival signature. The expression levels of genes within each signature were then averaged to create a “signature average” for each biopsy specimen. For the MMMLNP CHOP data set, the average was calculated for those array elements represented on the Affymetrix U133A microarray. 
     From the four prognostic clusters or signatures, two signatures, the stromal-1 and the GCB signatures were used to create the best two variable survival model. Neither the proliferation nor the MHC class II signatures added to the prognostic value of this two variable model. This bivariate model performed well in the MMMLNP CHOP cohort ( FIG. 9A ) and in the R-CHOP cohort ( FIG. 2A ). 
     The CHOP training set was used to discover and refine signatures that added to the prognostic significance of this bivariate model, and the resulting multivariate models were tested in the R-CHOP cohort. 563 genes were identified as adding to the model in the direction of adverse prognosis. These genes were clustered by hierarchical clustering, and three clusters of more than 10 genes with an average correlation of &gt;0.6 were identified. In addition, 542 genes were identified which added to the stromal-1 and GCB signature model in the direction of favorable prognosis. These genes were clustered, and two clusters of more than 10 genes with an average correlation of &gt;0.6 were identified. Signature averages were determined for these clusters, and three variable models containing the stromal-1 and GCB signature and each of the cluster averages were formed on the MMMLNP CHOP and R-CHOP data sets. Of the five cluster averages, two were found to add statistical significance (p&lt;0.02) in the MMMLNP CHOP data as compared to a model containing the stromal-1 and GCB signatures alone. By contrast, in the R-CHOP data, three of the five cluster averages were found to add significance (p&lt;0.02) to the bivariate model. One of these cluster averages added significantly to the bivariate model in both the MMMLNP CHOP and R-CHOP data. This signature, designated Signature 122, was also found to add to the stromal-1 and GCB signature far more significantly than any of the four other signatures on the LLMPP CHOP data and, thus, was retained for further analysis. 
     Signature 122 added significantly to the bivariate model in both the MMMLNP CHOP cohort (p=0.011) and in the R-CHOP cohort (p=0.001) ( FIGS. 9  B and  9 C). This Signature 122 positively correlated with the stromal-1 signature, although it was associated with adverse survival when added to the bivariate model. To further refine our model, we identified genes that were more correlated with Signature 122 than with the stromal-1 signature (p&lt;0.02). These genes were organized by hierarchical clustering, and three sets of correlated genes (r&gt;0.6) were observed. One of these clusters, the stromal-2 signature, added to the significance of the bivariate model in both the MMMLNP CHOP cohort (p=0.002) and the R-CHOP cohort (p&lt;0.001) ( FIGS. 2B and 9D ). 
     A multivariate survival model was formed by fitting a Cox model with the GCB, stromal-1, and stomal-2 signatures to the LLMPP CHOP cohort data shown in Table 3. This final multivariate model with its associated scaling coefficients was then evaluated on the MMLLMPP CHOP and R-CHOP cohort data sets. Survival predictor scores from the final model were used to divide the R-CHOP cohort into quartile groups with 3-year overall survival rates of 89%, 82%, 74%, and 48%, and 3-year progression-free survival rates of 84%, 69%, 61% and 33% ( FIG. 2B ). The survival predictor scores from the final model are illustrated in  FIG. 3  along with the three component signatures and representative genes of each signature. 
     
       
         
           
               
               
               
               
               
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                   
                 Time to 
                 Status at 
                 Time to death, 
                 Status at last 
                 Germinal 
                   
                   
                   
               
               
                   
                 death or last 
                 last follow up 
                 progression, or 
                 follow up 
                 Center 
                 Stromal-1 
                 Stromal-2 
               
               
                   
                 follow up 
                 (1 = dead, 
                 last follow up 
                 (1 = progressed or died, 
                 Signature 
                 Signature 
                 Signature 
                 Model 
               
               
                 Patient 
                 (years) 
                 0 = alive) 
                 (years) 
                 0 = no progression) 
                 Average 
                 Average 
                 Average 
                 Score 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 2 
                 2.75 
                 0 
                 2.75 
                 0 
                 9.238 
                 8.778 
                 7.475 
                 0.376 
               
               
                 3 
                 2.67 
                 0 
                 2.67 
                 0 
                 9.942 
                 8.227 
                 7.102 
                 0.387 
               
               
                 5 
                 1.27 
                 1 
                 0.72 
                 1 
                 8.859 
                 9.033 
                 8.716 
                 1.113 
               
               
                 21 
                 2.39 
                 0 
                 2.40 
                 0 
                 10.573 
                 8.519 
                 6.959 
                 −0.270 
               
               
                 22 
                 2.38 
                 0 
                 2.38 
                 0 
                 8.737 
                 8.686 
                 7.598 
                 0.761 
               
               
                 23 
                 2.52 
                 0 
                 2.52 
                 0 
                 10.694 
                 10.322 
                 8.817 
                 −0.897 
               
               
                 24 
                 5.11 
                 0 
                 5.11 
                 0 
                 11.376 
                 7.854 
                 7.598 
                 0.500 
               
               
                 26 
                 4.01 
                 0 
                 4.01 
                 0 
                 9.829 
                 9.956 
                 8.507 
                 −0.372 
               
               
                 28 
                 3.96 
                 0 
                 3.96 
                 0 
                 10.957 
                 9.277 
                 8.248 
                 −0.330 
               
               
                 41 
                 0.52 
                 1 
                 0.52 
                 1 
                 9.273 
                 9.437 
                 8.202 
                 0.183 
               
               
                 47 
                 1.53 
                 1 
                 0.77 
                 1 
                 9.548 
                 8.802 
                 8.061 
                 0.617 
               
               
                 48 
                 0.37 
                 1 
                 0.12 
                 1 
                 8.660 
                 8.279 
                 6.891 
                 0.729 
               
               
                 49 
                 2.37 
                 0 
                 2.35 
                 1 
                 10.915 
                 8.988 
                 6.847 
                 −0.965 
               
               
                 53 
                 3.89 
                 0 
                 2.23 
                 1 
                 9.530 
                 9.792 
                 9.693 
                 0.721 
               
               
                 61 
                 0.90 
                 1 
                 0.46 
                 1 
                 8.649 
                 8.038 
                 8.104 
                 1.798 
               
               
                 65 
                 4.04 
                 0 
                 4.04 
                 0 
                 10.744 
                 9.330 
                 7.930 
                 −0.508 
               
               
                 66 
                 4.04 
                 0 
                 4.04 
                 0 
                 10.714 
                 10.016 
                 7.536 
                 −1.459 
               
               
                 95 
                 0.62 
                 1 
                 0.44 
                 1 
                 9.244 
                 9.197 
                 8.105 
                 0.373 
               
               
                 96 
                 5.37 
                 0 
                 5.37 
                 0 
                 10.107 
                 8.723 
                 7.608 
                 0.157 
               
               
                 97 
                 5.07 
                 0 
                 5.07 
                 0 
                 9.777 
                 9.192 
                 7.359 
                 −0.349 
               
               
                 98 
                 0.94 
                 1 
                 0.59 
                 1 
                 8.794 
                 7.711 
                 7.367 
                 1.571 
               
               
                 99 
                 0.40 
                 1 
                 0.40 
                 1 
                 9.024 
                 9.272 
                 9.160 
                 1.101 
               
               
                 103 
                 0.03 
                 1 
                 0.02 
                 1 
                 8.883 
                 8.190 
                 7.742 
                 1.301 
               
               
                 104 
                 3.76 
                 0 
                 3.76 
                 0 
                 9.785 
                 9.866 
                 7.929 
                 −0.652 
               
               
                 106 
                 2.95 
                 0 
                 2.95 
                 0 
                 10.585 
                 7.797 
                 6.824 
                 0.367 
               
               
                 107 
                 2.94 
                 0 
                 2.94 
                 0 
                 11.535 
                 8.358 
                 6.660 
                 −0.711 
               
               
                 108 
                 2.73 
                 0 
                 2.73 
                 0 
                 9.653 
                 8.495 
                 7.550 
                 0.539 
               
               
                 109 
                 0.16 
                 1 
                 0.11 
                 1 
                 9.301 
                 9.376 
                 7.994 
                 0.092 
               
               
                 110 
                 2.46 
                 0 
                 2.46 
                 0 
                 10.254 
                 8.980 
                 7.324 
                 −0.357 
               
               
                 111 
                 2.44 
                 0 
                 2.44 
                 0 
                 10.137 
                 10.691 
                 8.948 
                 −0.949 
               
               
                 113 
                 2.12 
                 0 
                 2.12 
                 0 
                 10.746 
                 8.555 
                 6.942 
                 −0.390 
               
               
                 114 
                 1.98 
                 0 
                 0.88 
                 1 
                 8.562 
                 8.159 
                 7.120 
                 1.047 
               
               
                 115 
                 1.92 
                 0 
                 1.92 
                 0 
                 10.313 
                 9.385 
                 8.157 
                 −0.231 
               
               
                 118 
                 1.64 
                 0 
                 1.64 
                 0 
                 10.209 
                 10.194 
                 8.231 
                 −0.959 
               
               
                 119 
                 1.60 
                 0 
                 1.60 
                 0 
                 11.059 
                 8.852 
                 7.479 
                 −0.461 
               
               
                 1087 
                 0.05 
                 1 
                 0.05 
                 1 
                 8.756 
                 8.491 
                 7.949 
                 1.188 
               
               
                 1089 
                 5.12 
                 0 
                 1.27 
                 1 
                 9.863 
                 9.135 
                 8.034 
                 0.129 
               
               
                 1091 
                 5.15 
                 0 
                 5.15 
                 0 
                 10.454 
                 9.918 
                 8.742 
                 −0.437 
               
               
                 1092 
                 5.06 
                 0 
                 5.07 
                 0 
                 9.452 
                 9.467 
                 8.912 
                 0.556 
               
               
                 1093 
                 3.83 
                 1 
                 1.62 
                 1 
                 9.915 
                 9.138 
                 7.747 
                 −0.090 
               
               
                 1096 
                 4.02 
                 0 
                 4.02 
                 0 
                 8.887 
                 9.236 
                 7.795 
                 0.274 
               
               
                 1097 
                 1.26 
                 1 
                 1.08 
                 1 
                 11.219 
                 9.234 
                 8.321 
                 −0.347 
               
               
                 1098 
                 3.53 
                 0 
                 3.53 
                 0 
                 9.117 
                 9.236 
                 7.655 
                 0.082 
               
               
                 1099 
                 3.07 
                 0 
                 0.91 
                 1 
                 9.284 
                 8.798 
                 7.741 
                 0.515 
               
               
                 1101 
                 5.64 
                 0 
                 5.64 
                 0 
                 9.803 
                 9.466 
                 8.156 
                 −0.101 
               
               
                 1108 
                 3.30 
                 0 
                 3.30 
                 0 
                 9.195 
                 10.456 
                 9.065 
                 −0.237 
               
               
                 1109 
                 3.78 
                 0 
                 3.78 
                 0 
                 11.008 
                 10.051 
                 8.273 
                 −1.120 
               
               
                 1164 
                 0.19 
                 1 
                 0.16 
                 1 
                 9.242 
                 10.307 
                 10.548 
                 0.896 
               
               
                 1167 
                 1.49 
                 1 
                 0.45 
                 1 
                 9.809 
                 9.105 
                 8.784 
                 0.687 
               
               
                 1168 
                 0.42 
                 1 
                 0.30 
                 1 
                 8.718 
                 8.368 
                 7.149 
                 0.790 
               
               
                 1169 
                 1.71 
                 1 
                 1.22 
                 1 
                 11.512 
                 8.108 
                 7.507 
                 0.125 
               
               
                 1172 
                 2.82 
                 0 
                 2.82 
                 0 
                 11.137 
                 8.871 
                 8.153 
                 −0.057 
               
               
                 1173 
                 0.87 
                 1 
                 0.79 
                 1 
                 11.324 
                 9.914 
                 8.514 
                 −0.950 
               
               
                 1175 
                 1.06 
                 1 
                 0.56 
                 1 
                 9.107 
                 10.310 
                 9.063 
                 −0.053 
               
               
                 1179 
                 2.53 
                 0 
                 2.53 
                 0 
                 9.506 
                 9.437 
                 8.461 
                 0.260 
               
               
                 1181 
                 1.72 
                 0 
                 1.72 
                 0 
                 10.688 
                 9.018 
                 7.647 
                 −0.360 
               
               
                 1184 
                 4.74 
                 0 
                 2.97 
                 1 
                 10.812 
                 8.979 
                 7.922 
                 −0.187 
               
               
                 1185 
                 3.71 
                 0 
                 3.71 
                 0 
                 10.431 
                 8.397 
                 7.317 
                 0.156 
               
               
                 1186 
                 3.43 
                 0 
                 3.43 
                 0 
                 8.688 
                 8.944 
                 8.552 
                 1.164 
               
               
                 1187 
                 5.23 
                 0 
                 5.23 
                 0 
                 10.072 
                 10.192 
                 8.667 
                 −0.604 
               
               
                 1189 
                 5.13 
                 0 
                 5.13 
                 0 
                 10.109 
                 9.212 
                 7.967 
                 −0.097 
               
               
                 1190 
                 3.66 
                 0 
                 3.66 
                 0 
                 10.713 
                 10.409 
                 8.910 
                 −0.930 
               
               
                 1192 
                 0.16 
                 1 
                 0.16 
                 1 
                 8.825 
                 9.903 
                 8.061 
                 −0.199 
               
               
                 1195 
                 4.36 
                 0 
                 4.36 
                 0 
                 11.539 
                 7.567 
                 6.873 
                 0.234 
               
               
                 1197 
                 3.13 
                 0 
                 3.13 
                 0 
                 10.287 
                 10.365 
                 9.549 
                 −0.275 
               
               
                 1200 
                 0.31 
                 1 
                 0.31 
                 1 
                 9.432 
                 8.950 
                 9.805 
                 1.692 
               
               
                 1206 
                 6.51 
                 0 
                 6.51 
                 0 
                 10.410 
                 9.946 
                 8.925 
                 −0.323 
               
               
                 1211 
                 6.25 
                 0 
                 6.25 
                 0 
                 11.596 
                 7.908 
                 6.524 
                 −0.372 
               
               
                 1215 
                 5.35 
                 0 
                 5.35 
                 0 
                 10.504 
                 9.061 
                 7.550 
                 −0.392 
               
               
                 1216 
                 0.46 
                 1 
                 0.29 
                 1 
                 10.017 
                 9.010 
                 7.794 
                 0.028 
               
               
                 1219 
                 0.51 
                 1 
                 0.51 
                 1 
                 10.614 
                 10.014 
                 8.619 
                 −0.683 
               
               
                 1220 
                 2.24 
                 1 
                 2.25 
                 1 
                 8.850 
                 9.400 
                 8.036 
                 0.286 
               
               
                 1221 
                 3.94 
                 0 
                 3.95 
                 0 
                 8.777 
                 7.489 
                 6.672 
                 1.334 
               
               
                 1222 
                 3.53 
                 0 
                 3.53 
                 0 
                 10.463 
                 9.310 
                 7.019 
                 −0.986 
               
               
                 1224 
                 3.22 
                 0 
                 2.11 
                 1 
                 9.751 
                 9.505 
                 8.453 
                 0.082 
               
               
                 1225 
                 2.95 
                 0 
                 2.95 
                 0 
                 8.613 
                 8.313 
                 7.668 
                 1.240 
               
               
                 1226 
                 0.08 
                 1 
                 0.08 
                 1 
                 9.229 
                 8.851 
                 7.950 
                 0.625 
               
               
                 1228 
                 2.78 
                 0 
                 0.99 
                 1 
                 11.532 
                 8.261 
                 6.932 
                 −0.428 
               
               
                 1230 
                 0.59 
                 1 
                 0.54 
                 1 
                 9.369 
                 6.951 
                 6.956 
                 1.825 
               
               
                 1231 
                 1.41 
                 0 
                 1.41 
                 0 
                 10.248 
                 8.788 
                 8.011 
                 0.303 
               
               
                 1232 
                 2.49 
                 0 
                 0.68 
                 1 
                 10.362 
                 8.528 
                 7.975 
                 0.495 
               
               
                 1233 
                 2.50 
                 0 
                 2.50 
                 0 
                 9.239 
                 10.581 
                 8.470 
                 −0.784 
               
               
                 1236 
                 2.56 
                 0 
                 2.56 
                 0 
                 9.156 
                 10.000 
                 7.805 
                 −0.608 
               
               
                 1238 
                 0.16 
                 1 
                 0.16 
                 1 
                 9.488 
                 9.055 
                 8.256 
                 0.517 
               
               
                 1239 
                 2.24 
                 0 
                 2.24 
                 0 
                 8.886 
                 8.978 
                 7.838 
                 0.564 
               
               
                 1240 
                 1.48 
                 0 
                 1.48 
                 0 
                 10.474 
                 9.073 
                 7.702 
                 −0.288 
               
               
                 1241 
                 1.41 
                 1 
                 1.17 
                 1 
                 9.044 
                 9.054 
                 7.451 
                 0.160 
               
               
                 1251 
                 2.72 
                 0 
                 2.72 
                 0 
                 8.410 
                 8.687 
                 7.082 
                 0.549 
               
               
                 1252 
                 0.01 
                 1 
                 0.01 
                 1 
                 11.167 
                 8.070 
                 7.358 
                 0.206 
               
               
                 1255 
                 5.17 
                 0 
                 5.17 
                 0 
                 9.501 
                 9.411 
                 7.887 
                 −0.099 
               
               
                 1271 
                 4.72 
                 0 
                 4.73 
                 0 
                 10.718 
                 8.452 
                 7.060 
                 −0.194 
               
               
                 1272 
                 5.68 
                 0 
                 5.68 
                 0 
                 9.161 
                 9.080 
                 7.668 
                 0.231 
               
               
                 1275 
                 1.89 
                 1 
                 1.48 
                 1 
                 9.257 
                 8.559 
                 8.607 
                 1.354 
               
               
                 1277 
                 5.06 
                 0 
                 5.07 
                 0 
                 11.091 
                 9.938 
                 8.274 
                 −1.038 
               
               
                 1279 
                 4.87 
                 0 
                 4.87 
                 0 
                 9.309 
                 10.085 
                 9.676 
                 0.504 
               
               
                 1281 
                 3.36 
                 0 
                 not available (n/a) 
                 n/a 
                 9.535 
                 9.969 
                 9.090 
                 0.132 
               
               
                 1284 
                 3.51 
                 0 
                 3.51 
                 0 
                 10.922 
                 9.680 
                 8.481 
                 −0.567 
               
               
                 1288 
                 1.54 
                 0 
                 n/a 
                 n/a 
                 9.430 
                 8.896 
                 8.037 
                 0.554 
               
               
                 1289 
                 0.03 
                 1 
                 0.03 
                 1 
                 8.915 
                 9.052 
                 8.002 
                 0.589 
               
               
                 1290 
                 5.23 
                 0 
                 5.23 
                 0 
                 10.432 
                 10.426 
                 8.154 
                 −1.340 
               
               
                 1291 
                 0.04 
                 1 
                 0.04 
                 1 
                 11.319 
                 8.246 
                 7.323 
                 −0.059 
               
               
                 1292 
                 0.10 
                 1 
                 0.10 
                 1 
                 8.667 
                 8.764 
                 8.110 
                 1.058 
               
               
                 1293 
                 4.81 
                 0 
                 4.81 
                 0 
                 11.116 
                 9.842 
                 8.083 
                 −1.081 
               
               
                 1294 
                 0.53 
                 1 
                 0.53 
                 1 
                 10.138 
                 10.181 
                 8.501 
                 −0.733 
               
               
                 1295 
                 5.16 
                 0 
                 5.17 
                 0 
                 9.445 
                 9.694 
                 7.739 
                 −0.463 
               
               
                 1296 
                 4.79 
                 0 
                 4.79 
                 0 
                 10.228 
                 9.064 
                 8.852 
                 0.600 
               
               
                 1297 
                 4.24 
                 0 
                 4.24 
                 0 
                 9.524 
                 7.990 
                 7.008 
                 0.740 
               
               
                 1298 
                 4.56 
                 0 
                 4.56 
                 0 
                 9.022 
                 9.000 
                 7.695 
                 0.389 
               
               
                 1331 
                 3.29 
                 0 
                 3.29 
                 0 
                 11.004 
                 9.488 
                 8.289 
                 −0.536 
               
               
                 1334 
                 2.87 
                 0 
                 2.87 
                 0 
                 11.434 
                 9.509 
                 8.109 
                 −0.859 
               
               
                 1335 
                 1.38 
                 1 
                 0.90 
                 1 
                 9.586 
                 8.545 
                 7.423 
                 0.431 
               
               
                 1336 
                 2.44 
                 0 
                 2.44 
                 0 
                 10.844 
                 9.704 
                 7.706 
                 −1.082 
               
               
                 1337 
                 0.02 
                 1 
                 0.02 
                 1 
                 8.521 
                 7.788 
                 7.860 
                 1.941 
               
               
                 1449 
                 1.62 
                 0 
                 1.62 
                 0 
                 9.604 
                 8.463 
                 8.030 
                 0.917 
               
               
                 1450 
                 1.30 
                 0 
                 0.53 
                 1 
                 8.571 
                 8.112 
                 7.241 
                 1.173 
               
               
                 1451 
                 1.84 
                 0 
                 1.85 
                 0 
                 10.637 
                 9.205 
                 7.759 
                 −0.452 
               
               
                 1453 
                 1.71 
                 0 
                 1.71 
                 0 
                 10.964 
                 9.089 
                 8.226 
                 −0.157 
               
               
                 1454 
                 0.62 
                 0 
                 0.62 
                 0 
                 11.106 
                 8.514 
                 7.604 
                 −0.052 
               
               
                 1553 
                 2.93 
                 0 
                 1.92 
                 1 
                 8.975 
                 9.284 
                 7.475 
                 −0.029 
               
               
                 1612 
                 5.37 
                 0 
                 5.37 
                 0 
                 10.526 
                 9.471 
                 7.809 
                 −0.643 
               
               
                 1613 
                 5.81 
                 0 
                 n/a 
                 n/a 
                 10.868 
                 9.695 
                 7.730 
                 −1.067 
               
               
                 1614 
                 4.36 
                 1 
                 4.36 
                 1 
                 10.358 
                 9.226 
                 8.765 
                 0.322 
               
               
                 1617 
                 0.52 
                 0 
                 0.52 
                 0 
                 10.332 
                 8.723 
                 7.180 
                 −0.227 
               
               
                 1618 
                 1.70 
                 0 
                 0.98 
                 1 
                 11.233 
                 8.956 
                 7.852 
                 −0.387 
               
               
                 1619 
                 0.25 
                 1 
                 0.25 
                 1 
                 8.646 
                 8.028 
                 7.123 
                 1.146 
               
               
                 1620 
                 2.17 
                 0 
                 2.17 
                 0 
                 11.647 
                 8.385 
                 7.343 
                 −0.325 
               
               
                 1623 
                 2.80 
                 0 
                 2.80 
                 0 
                 9.611 
                 9.484 
                 8.249 
                 0.024 
               
               
                 1626 
                 1.76 
                 0 
                 1.76 
                 0 
                 11.236 
                 9.495 
                 8.108 
                 −0.763 
               
               
                 1628 
                 3.13 
                 0 
                 1.23 
                 1 
                 8.714 
                 7.972 
                 7.149 
                 1.192 
               
               
                 1645 
                 2.85 
                 0 
                 2.85 
                 0 
                 10.146 
                 9.476 
                 8.914 
                 0.258 
               
               
                 1647 
                 2.79 
                 0 
                 2.80 
                 0 
                 10.485 
                 10.495 
                 8.707 
                 −1.058 
               
               
                 1650 
                 0.75 
                 1 
                 0.75 
                 1 
                 8.830 
                 7.346 
                 6.486 
                 1.333 
               
               
                 1651 
                 1.66 
                 0 
                 1.66 
                 0 
                 9.190 
                 7.949 
                 6.829 
                 0.801 
               
               
                 1652 
                 1.64 
                 0 
                 n/a 
                 n/a 
                 8.798 
                 8.943 
                 8.331 
                 0.969 
               
               
                 1702 
                 1.05 
                 0 
                 1.05 
                 1 
                 9.008 
                 8.217 
                 8.078 
                 1.447 
               
               
                 1703 
                 0.70 
                 1 
                 0.70 
                 1 
                 9.499 
                 8.637 
                 7.790 
                 0.621 
               
               
                 1704 
                 3.14 
                 0 
                 3.14 
                 0 
                 9.908 
                 9.231 
                 7.503 
                 −0.347 
               
               
                 1705 
                 3.94 
                 0 
                 3.94 
                 0 
                 8.933 
                 8.445 
                 8.187 
                 1.321 
               
               
                 1707 
                 2.80 
                 0 
                 2.80 
                 0 
                 10.610 
                 9.348 
                 7.872 
                 −0.510 
               
               
                 1742 
                 3.27 
                 0 
                 n/a 
                 n/a 
                 10.033 
                 8.715 
                 7.412 
                 0.063 
               
               
                 1746 
                 1.91 
                 0 
                 1.55 
                 1 
                 9.249 
                 8.705 
                 8.205 
                 0.937 
               
               
                 1747 
                 1.48 
                 0 
                 1.48 
                 0 
                 10.162 
                 8.866 
                 7.602 
                 −0.016 
               
               
                 1756 
                 3.47 
                 0 
                 3.47 
                 0 
                 10.815 
                 9.638 
                 7.248 
                 −1.312 
               
               
                 1761 
                 0.23 
                 1 
                 0.23 
                 1 
                 9.842 
                 10.192 
                 8.664 
                 −0.511 
               
               
                 1762 
                 5.20 
                 0 
                 5.20 
                 0 
                 10.583 
                 9.333 
                 7.445 
                 −0.772 
               
               
                 1763 
                 5.51 
                 0 
                 5.51 
                 0 
                 8.917 
                 8.925 
                 8.084 
                 0.771 
               
               
                 1766 
                 1.59 
                 0 
                 1.59 
                 0 
                 10.919 
                 10.037 
                 8.389 
                 −0.990 
               
               
                 1782 
                 1.09 
                 0 
                 1.09 
                 0 
                 10.753 
                 9.600 
                 8.332 
                 −0.516 
               
               
                 1788 
                 0.39 
                 1 
                 0.24 
                 1 
                 10.364 
                 8.738 
                 8.914 
                 0.915 
               
               
                 1861 
                 0.56 
                 1 
                 0.19 
                 1 
                 9.728 
                 8.604 
                 7.594 
                 0.427 
               
               
                 1867 
                 1.17 
                 1 
                 0.38 
                 1 
                 8.903 
                 11.501 
                 10.559 
                 −0.166 
               
               
                 1916 
                 1.41 
                 0 
                 n/a 
                 n/a 
                 9.295 
                 11.197 
                 11.508 
                 0.619 
               
               
                 1920 
                 1.32 
                 0 
                 1.32 
                 0 
                 10.165 
                 9.630 
                 8.789 
                 0.009 
               
               
                 1927 
                 1.53 
                 0 
                 1.53 
                 0 
                 9.195 
                 10.261 
                 9.791 
                 0.451 
               
               
                 1928 
                 0.72 
                 0 
                 0.72 
                 0 
                 9.769 
                 8.510 
                 7.330 
                 0.328 
               
               
                 1939 
                 0.47 
                 1 
                 0.47 
                 1 
                 9.097 
                 9.363 
                 7.647 
                 −0.043 
               
               
                 2002 
                 1.29 
                 0 
                 1.30 
                 0 
                 9.469 
                 9.542 
                 8.600 
                 0.262 
               
               
                 2006 
                 1.23 
                 0 
                 1.23 
                 0 
                 10.434 
                 8.223 
                 7.162 
                 0.227 
               
               
                 2067 
                 2.18 
                 0 
                 2.18 
                 0 
                 10.244 
                 11.186 
                 9.391 
                 −1.197 
               
               
                 2070 
                 0.31 
                 0 
                 0.12 
                 1 
                 10.486 
                 10.680 
                 10.353 
                 −0.135 
               
               
                 2162 
                 0.38 
                 1 
                 0.38 
                 1 
                 10.934 
                 10.020 
                 7.960 
                 −1.268 
               
               
                 2270 
                 1.59 
                 0 
                 1.59 
                 0 
                 10.117 
                 9.904 
                 8.506 
                 −0.440 
               
               
                 2271 
                 1.60 
                 0 
                 1.60 
                 0 
                 8.995 
                 9.349 
                 8.261 
                 0.428 
               
               
                 2274 
                 0.41 
                 0 
                 0.41 
                 0 
                 8.863 
                 7.623 
                 7.222 
                 1.533 
               
               
                 2283 
                 1.19 
                 0 
                 1.19 
                 0 
                 10.501 
                 8.361 
                 6.741 
                 −0.226 
               
               
                 2291 
                 0.87 
                 1 
                 0.85 
                 1 
                 10.732 
                 10.184 
                 9.436 
                 −0.353 
               
               
                 2299 
                 0.93 
                 0 
                 0.93 
                 0 
                 10.661 
                 9.905 
                 8.189 
                 −0.883 
               
               
                 2301 
                 0.61 
                 0 
                 0.61 
                 0 
                 9.852 
                 9.903 
                 8.352 
                 −0.432 
               
               
                 2306 
                 0.68 
                 0 
                 0.68 
                 0 
                 8.586 
                 8.759 
                 8.191 
                 1.151 
               
               
                 2309 
                 0.43 
                 0 
                 0.43 
                 0 
                 10.839 
                 7.671 
                 6.860 
                 0.413 
               
               
                 2311 
                 0.80 
                 0 
                 0.80 
                 0 
                 10.901 
                 7.797 
                 6.912 
                 0.294 
               
               
                 2318 
                 0.99 
                 0 
                 0.99 
                 0 
                 10.283 
                 9.403 
                 8.655 
                 0.100 
               
               
                 2321 
                 0.82 
                 0 
                 0.82 
                 0 
                 9.691 
                 8.956 
                 7.404 
                 −0.044 
               
               
                 2411 
                 0.67 
                 0 
                 0.67 
                 0 
                 8.986 
                 8.383 
                 7.854 
                 1.137 
               
               
                 2415 
                 0.62 
                 0 
                 0.62 
                 0 
                 9.296 
                 10.509 
                 9.551 
                 −0.005 
               
               
                 2444 
                 3.99 
                 0 
                 3.99 
                 0 
                 10.154 
                 9.871 
                 9.026 
                 −0.071 
               
               
                 2445 
                 3.36 
                 0 
                 3.36 
                 0 
                 8.788 
                 8.184 
                 7.964 
                 1.497 
               
               
                 2479 
                 0.51 
                 0 
                 0.51 
                 0 
                 11.151 
                 9.023 
                 8.199 
                 −0.186 
               
               
                 2482 
                 4.54 
                 0 
                 4.54 
                 0 
                 10.373 
                 9.847 
                 8.208 
                 −0.691 
               
               
                 2483 
                 3.89 
                 1 
                 3.89 
                 1 
                 9.241 
                 8.902 
                 7.742 
                 0.428 
               
               
                 2484 
                 2.69 
                 1 
                 1.90 
                 1 
                 10.279 
                 9.619 
                 8.312 
                 −0.349 
               
               
                 2485 
                 4.43 
                 0 
                 4.43 
                 0 
                 9.957 
                 9.865 
                 8.439 
                 −0.378 
               
               
                 2486 
                 4.37 
                 0 
                 n/a 
                 n/a 
                 10.698 
                 10.203 
                 8.041 
                 −1.301 
               
               
                 2487 
                 4.34 
                 0 
                 4.34 
                 0 
                 11.227 
                 9.909 
                 8.260 
                 −1.076 
               
               
                 2488 
                 4.20 
                 0 
                 4.21 
                 0 
                 9.510 
                 8.709 
                 7.615 
                 0.426 
               
               
                 2490 
                 4.02 
                 0 
                 4.02 
                 0 
                 10.510 
                 10.961 
                 8.956 
                 −1.374 
               
               
                 2491 
                 0.50 
                 1 
                 0.25 
                 1 
                 9.047 
                 8.554 
                 7.624 
                 0.784 
               
               
                 2492 
                 3.96 
                 0 
                 3.96 
                 0 
                 9.904 
                 10.901 
                 9.140 
                 −0.935 
               
               
                 2497 
                 3.44 
                 0 
                 3.44 
                 0 
                 9.221 
                 9.438 
                 8.065 
                 0.111 
               
               
                 2498 
                 3.37 
                 0 
                 3.37 
                 0 
                 9.318 
                 9.427 
                 8.003 
                 0.040 
               
               
                 2500 
                 3.31 
                 0 
                 3.31 
                 0 
                 11.014 
                 9.406 
                 7.375 
                 −1.074 
               
               
                 2501 
                 3.28 
                 0 
                 n/a 
                 n/a 
                 8.822 
                 8.551 
                 7.750 
                 0.966 
               
               
                 2503 
                 2.99 
                 0 
                 2.99 
                 0 
                 8.301 
                 7.967 
                 6.929 
                 1.222 
               
               
                 2504 
                 2.78 
                 0 
                 2.78 
                 0 
                 10.145 
                 8.004 
                 7.017 
                 0.472 
               
               
                 2505 
                 2.76 
                 0 
                 2.76 
                 0 
                 11.036 
                 8.442 
                 7.136 
                 −0.266 
               
               
                 2507 
                 0.86 
                 1 
                 0.54 
                 1 
                 9.737 
                 9.475 
                 8.988 
                 0.480 
               
               
                 2508 
                 2.58 
                 0 
                 2.58 
                 0 
                 8.678 
                 9.389 
                 8.230 
                 0.498 
               
               
                 2509 
                 0.96 
                 1 
                 0.76 
                 1 
                 8.895 
                 10.441 
                 9.088 
                 −0.081 
               
               
                 2511 
                 1.55 
                 1 
                 1.06 
                 1 
                 9.225 
                 9.267 
                 9.191 
                 1.042 
               
               
                 2512 
                 2.45 
                 0 
                 2.45 
                 0 
                 11.047 
                 10.465 
                 9.337 
                 −0.838 
               
               
                 2513 
                 0.61 
                 1 
                 0.61 
                 1 
                 10.855 
                 10.378 
                 8.395 
                 −1.305 
               
               
                 2514 
                 2.18 
                 0 
                 2.18 
                 0 
                 10.477 
                 9.832 
                 7.498 
                 −1.198 
               
               
                 2515 
                 2.13 
                 0 
                 2.13 
                 0 
                 9.295 
                 10.519 
                 9.788 
                 0.145 
               
               
                 2516 
                 2.07 
                 0 
                 2.07 
                 0 
                 10.575 
                 10.592 
                 8.642 
                 −1.238 
               
               
                 2517 
                 2.04 
                 0 
                 0.76 
                 1 
                 9.385 
                 9.163 
                 8.328 
                 0.498 
               
               
                 2584 
                 0.68 
                 0 
                 0.68 
                 0 
                 10.759 
                 9.356 
                 8.135 
                 −0.404 
               
               
                 2599 
                 4.05 
                 0 
                 4.05 
                 0 
                 10.629 
                 9.158 
                 7.724 
                 −0.425 
               
               
                 2600 
                 1.01 
                 1 
                 0.54 
                 1 
                 9.785 
                 8.619 
                 7.291 
                 0.184 
               
               
                 2601 
                 1.22 
                 1 
                 0.88 
                 1 
                 9.385 
                 8.044 
                 7.178 
                 0.859 
               
               
                 2603 
                 4.43 
                 0 
                 4.43 
                 0 
                 9.582 
                 10.707 
                 9.803 
                 −0.156 
               
               
                 2604 
                 0.84 
                 0 
                 0.36 
                 1 
                 9.844 
                 10.511 
                 8.382 
                 −1.026 
               
               
                 2609 
                 8.89 
                 0 
                 2.55 
                 1 
                 8.981 
                 8.775 
                 7.506 
                 0.507 
               
               
                 2610 
                 0.74 
                 0 
                 0.74 
                 0 
                 10.793 
                 8.964 
                 7.421 
                 −0.502 
               
               
                 2611 
                 0.66 
                 0 
                 0.66 
                 0 
                 10.353 
                 10.233 
                 9.032 
                 −0.518 
               
               
                 2612 
                 1.17 
                 1 
                 1.13 
                 1 
                 10.290 
                 9.028 
                 8.287 
                 0.230 
               
               
                 2613 
                 1.66 
                 0 
                 1.66 
                 0 
                 10.997 
                 9.089 
                 7.749 
                 −0.493 
               
               
                 2614 
                 0.21 
                 1 
                 0.21 
                 1 
                 8.768 
                 7.850 
                 7.100 
                 1.261 
               
               
                 2615 
                 0.48 
                 0 
                 0.48 
                 0 
                 11.359 
                 9.470 
                 7.647 
                 −1.100 
               
               
                 2639 
                 10.29 
                 0 
                 10.30  
                 0 
                 11.085 
                 10.385 
                 8.003 
                 −1.674 
               
               
                 2641 
                 1.38 
                 0 
                 1.38 
                 0 
                 9.199 
                 8.818 
                 7.340 
                 0.259 
               
               
                 2642 
                 3.67 
                 0 
                 3.67 
                 0 
                 10.731 
                 8.777 
                 7.167 
                 −0.458 
               
               
                 2643 
                 5.49 
                 0 
                 5.49 
                 0 
                 10.236 
                 10.578 
                 8.473 
                 −1.197 
               
               
                 2645 
                 0.19 
                 0 
                 n/a 
                 n/a 
                 11.130 
                 9.997 
                 8.254 
                 −1.129 
               
               
                 2646 
                 0.18 
                 1 
                 0.18 
                 1 
                 8.893 
                 7.648 
                 6.871 
                 1.260 
               
               
                 2648 
                 0.25 
                 0 
                 0.25 
                 0 
                 8.855 
                 7.745 
                 7.060 
                 1.303 
               
               
                 2649 
                 2.13 
                 0 
                 2.13 
                 0 
                 9.688 
                 10.354 
                 9.885 
                 0.214 
               
               
                 2650 
                 2.43 
                 0 
                 n/a 
                 n/a 
                 10.007 
                 10.052 
                 8.861 
                 −0.305 
               
               
                 2651 
                 1.61 
                 0 
                 n/a 
                 n/a 
                 10.660 
                 9.452 
                 7.831 
                 −0.665 
               
               
                 2652 
                 1.84 
                 0 
                 1.84 
                 0 
                 11.378 
                 9.247 
                 7.684 
                 −0.856 
               
               
                 2653 
                 1.88 
                 0 
                 1.88 
                 0 
                 11.182 
                 9.638 
                 7.781 
                 −1.106 
               
               
                 2654 
                 1.43 
                 0 
                 1.43 
                 0 
                 8.791 
                 9.395 
                 8.905 
                 0.902 
               
               
                 2813 
                 3.97 
                 0 
                 3.97 
                 0 
                 10.701 
                 9.366 
                 8.258 
                 −0.306 
               
               
                 2814 
                 0.81 
                 1 
                 0.70 
                 1 
                 10.561 
                 9.176 
                 9.275 
                 0.632 
               
               
                   
               
            
           
         
       
     
     The International Prognostic Index (IPI), which is based on 5 clinical variables, predicts survival in both CHOP-treated and R-CHOP-treated patients (Shipp et al.,  N. Engl. J. Med.,  329:987-94 (1993); Sehn et al.,  Blood,  109: 1857-61 (2007)). The inventive gene expression-based survival model retained its prognostic significance among R-CHOP-treated patients segregated according to IPI into high, intermediate and low IPI risk groups, both as originally defined (Shipp et al., supra) (p&lt;0.001) ( FIG. 2C ) and as recently modified for R-CHOP-treated DLBCL (Sehn et al., supra) (p&lt;0.001) ( FIG. 10 ). 
     The foregoing results indicate that the gene expression-based multivariate model can be used to identify large disparities in survival among patients with different DLBCL gene signature profiles. Thus, survival predictor scores were used to divide patients into least and most favorable quartile groups having 3-year progression-free survival rates of 33% and 84%, respectively. Given its statistical independence from the IPI, the gene expression-based survival predictor provides a complementary view of DLBCL variation that can be considered when analyzing data from DLBCL clinical trials. Additionally, the foregoing results indicate that whole-genome gene expression profiles in conjunction with the survival model described herein can be used to provide optimal predictions of expected survival outcomes for subjects suffering from DLBCL. 
     Example 3 
     This example demonstrates the use of a survival predictor score to predict the probability of progression free and overall survival outcomes at a period of time t following R-CHOP treatment in accordance with the invention. 
     RNA is isolated from a patient&#39;s DLBCL biopsy and hybridized to a U133+ array from Affymetrix (Santa Clara, Calif.). The array is scanned, and MAS 5.0 algorithm is applied to obtain signal values normalized to a target intensity of 500. Signal values are log 2 transformed to intensity values. For genes of interest with multiple probe sets, the intensity value of the multiple probe sets are averaged to obtain a single intensity value for each gene. The single intensity values of genes in the GCB signature are averaged to obtain a GCB signature average of 9.2. The single intensity values of genes in the stromal-1 signature are averaged to obtain a stromal-1 signature average of 8.5. The single intensity values of genes in the stromal-2 signature are averaged to obtain a stromal-2 signature average of 7.2. 
     The patient&#39;s survival predictor score is calculated using the following equation
 
8.11−[0.419*( GCB  signature average)]−[1.015*(stromal-1 signature average)]+[0.675*(stromal-2 signature average)],such that the survival predictor score=8.11−[0.419*(9.2)]−[1.015*(8.5)]+[0.675*(7.2)]=0.389
 
     Table 4 includes values from a progression free survival curve generated using baseline hazard functions calculated from the R-CHOP patient data described in Table 3. The curve was generated in accordance with the methods of Kalbfleisch and Prentice,  Biometrika,  60: 267-279 (1973), which involves maximizing the full likelihood, under the assumption that the true scaling coefficients were equal to prior estimates. In Table 4, F 0 (t) is the probability of progression free survival for each indicated time period following R-CHOP treatment (t-RCHOP). 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 4 
               
               
                   
                   
               
               
                   
                 t-RCHOP (years) 
                 F 0 (t) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 0.000 
                 1.000 
               
               
                   
                 0.008 
                 0.997 
               
               
                   
                 0.016 
                 0.993 
               
               
                   
                 0.025 
                 0.990 
               
               
                   
                 0.030 
                 0.987 
               
               
                   
                 0.036 
                 0.983 
               
               
                   
                 0.049 
                 0.980 
               
               
                   
                 0.082 
                 0.977 
               
               
                   
                 0.096 
                 0.973 
               
               
                   
                 0.107 
                 0.970 
               
               
                   
                 0.118 
                 0.967 
               
               
                   
                 0.120 
                 0.963 
               
               
                   
                 0.156 
                 0.960 
               
               
                   
                 0.156 
                 0.956 
               
               
                   
                 0.159 
                 0.953 
               
               
                   
                 0.178 
                 0.950 
               
               
                   
                 0.192 
                 0.946 
               
               
                   
                 0.211 
                 0.943 
               
               
                   
                 0.233 
                 0.939 
               
               
                   
                 0.241 
                 0.936 
               
               
                   
                 0.246 
                 0.932 
               
               
                   
                 0.252 
                 0.928 
               
               
                   
                 0.290 
                 0.925 
               
               
                   
                 0.298 
                 0.921 
               
               
                   
                 0.307 
                 0.918 
               
               
                   
                 0.364 
                 0.914 
               
               
                   
                 0.381 
                 0.910 
               
               
                   
                 0.381 
                 0.907 
               
               
                   
                 0.400 
                 0.903 
               
               
                   
                 0.441 
                 0.899 
               
               
                   
                 0.446 
                 0.895 
               
               
                   
                 0.463 
                 0.891 
               
               
                   
                 0.468 
                 0.887 
               
               
                   
                 0.515 
                 0.884 
               
               
                   
                 0.517 
                 0.880 
               
               
                   
                 0.531 
                 0.876 
               
               
                   
                 0.534 
                 0.872 
               
               
                   
                 0.537 
                 0.868 
               
               
                   
                 0.537 
                 0.864 
               
               
                   
                 0.539 
                 0.860 
               
               
                   
                 0.561 
                 0.856 
               
               
                   
                 0.586 
                 0.852 
               
               
                   
                 0.611 
                 0.848 
               
               
                   
                 0.679 
                 0.843 
               
               
                   
                 0.698 
                 0.839 
               
               
                   
                 0.698 
                 0.834 
               
               
                   
                 0.720 
                 0.830 
               
               
                   
                 0.747 
                 0.826 
               
               
                   
                 0.756 
                 0.821 
               
               
                   
                 0.761 
                 0.816 
               
               
                   
                 0.767 
                 0.812 
               
               
                   
                 0.786 
                 0.807 
               
               
                   
                 0.849 
                 0.803 
               
               
                   
                 0.879 
                 0.798 
               
               
                   
                 0.884 
                 0.793 
               
               
                   
                 0.898 
                 0.789 
               
               
                   
                 0.912 
                 0.784 
               
               
                   
                 0.977 
                 0.779 
               
               
                   
                 0.986 
                 0.774 
               
               
                   
                 1.046 
                 0.770 
               
               
                   
                 1.057 
                 0.765 
               
               
                   
                 1.076 
                 0.760 
               
               
                   
                 1.128 
                 0.755 
               
               
                   
                 1.166 
                 0.750 
               
               
                   
                 1.216 
                 0.745 
               
               
                   
                 1.227 
                 0.740 
               
               
                   
                 1.270 
                 0.735 
               
               
                   
                 1.481 
                 0.729 
               
               
                   
                 1.547 
                 0.724 
               
               
                   
                 1.624 
                 0.718 
               
               
                   
                 1.900 
                 0.711 
               
               
                   
                 1.919 
                 0.705 
               
               
                   
                 2.105 
                 0.699 
               
               
                   
                 2.231 
                 0.692 
               
               
                   
                 2.245 
                 0.685 
               
               
                   
                 2.352 
                 0.678 
               
               
                   
                 2.546 
                 0.671 
               
               
                   
                 2.968 
                 0.662 
               
               
                   
                 3.890 
                 0.648 
               
               
                   
                 4.364 
                 0.623 
               
               
                   
                   
               
            
           
         
       
     
     The patient&#39;s probability of 2 year progression free survival is calculated using the equation: P(PFS)=F 0 (t) (exp(0.976*survival predictor score)) , where F 0 (t) is the F 0 (t) value that corresponds to the largest time value smaller than 2 years in the progression free survival curve. In Table 4, the largest time value smaller than 2 is 1.919, and the corresponding PF 0 (t) value is 0.705. Accordingly, the patient&#39;s probability of 2 year progression free survival P(PFS)=0.705 (exp(0.976*survival predictor score)) =0.705 1.462 =0.600 or about 60%. 
     Table 5 includes values from an overall survival curve generated using baseline hazard functions calculated from the R-CHOP patient data described in Table 3. The curve was made according to the method of Kalbfleisch and Prentice,  Biometrika,  60: 267-279 (1973), which involves maximizing the full likelihood, under the assumption that the true scaling coefficients were equal to our estimates. In Table 5, OS 0 (t) is the probability of overall survival for each indicated time period following R-CHOP treatment (t-RCHOP). 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                 t-RCHOP (years) 
                 OS 0 (t) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 0.000 
                 1.000 
               
               
                   
                 0.008 
                 0.997 
               
               
                   
                 0.016 
                 0.994 
               
               
                   
                 0.030 
                 0.991 
               
               
                   
                 0.033 
                 0.988 
               
               
                   
                 0.036 
                 0.984 
               
               
                   
                 0.049 
                 0.981 
               
               
                   
                 0.082 
                 0.978 
               
               
                   
                 0.096 
                 0.975 
               
               
                   
                 0.156 
                 0.972 
               
               
                   
                 0.156 
                 0.969 
               
               
                   
                 0.159 
                 0.965 
               
               
                   
                 0.178 
                 0.962 
               
               
                   
                 0.192 
                 0.959 
               
               
                   
                 0.211 
                 0.956 
               
               
                   
                 0.233 
                 0.952 
               
               
                   
                 0.246 
                 0.949 
               
               
                   
                 0.307 
                 0.946 
               
               
                   
                 0.367 
                 0.942 
               
               
                   
                 0.380 
                 0.939 
               
               
                   
                 0.386 
                 0.935 
               
               
                   
                 0.402 
                 0.932 
               
               
                   
                 0.416 
                 0.928 
               
               
                   
                 0.463 
                 0.925 
               
               
                   
                 0.468 
                 0.921 
               
               
                   
                 0.504 
                 0.918 
               
               
                   
                 0.515 
                 0.914 
               
               
                   
                 0.517 
                 0.910 
               
               
                   
                 0.531 
                 0.907 
               
               
                   
                 0.556 
                 0.903 
               
               
                   
                 0.586 
                 0.900 
               
               
                   
                 0.610 
                 0.896 
               
               
                   
                 0.619 
                 0.892 
               
               
                   
                 0.698 
                 0.888 
               
               
                   
                 0.747 
                 0.885 
               
               
                   
                 0.807 
                 0.881 
               
               
                   
                 0.862 
                 0.877 
               
               
                   
                 0.868 
                 0.873 
               
               
                   
                 0.873 
                 0.869 
               
               
                   
                 0.895 
                 0.864 
               
               
                   
                 0.944 
                 0.860 
               
               
                   
                 0.963 
                 0.856 
               
               
                   
                 1.010 
                 0.852 
               
               
                   
                 1.057 
                 0.848 
               
               
                   
                 1.169 
                 0.843 
               
               
                   
                 1.169 
                 0.839 
               
               
                   
                 1.215 
                 0.835 
               
               
                   
                 1.262 
                 0.830 
               
               
                   
                 1.273 
                 0.826 
               
               
                   
                 1.382 
                 0.821 
               
               
                   
                 1.412 
                 0.817 
               
               
                   
                 1.492 
                 0.812 
               
               
                   
                 1.527 
                 0.807 
               
               
                   
                 1.552 
                 0.802 
               
               
                   
                 1.708 
                 0.796 
               
               
                   
                 1.889 
                 0.791 
               
               
                   
                 2.244 
                 0.784 
               
               
                   
                 2.693 
                 0.777 
               
               
                   
                 3.826 
                 0.763 
               
               
                   
                 3.889 
                 0.749 
               
               
                   
                 4.363 
                 0.724 
               
               
                   
                   
               
            
           
         
       
     
     The patient&#39;s probability of 2 year overall survival is calculated using the equation: P(OS)=OS 0 (t) (exp(survival predictor score)) , where OS 0 (t) is the value that corresponds to the largest time value in the overall survival curve which is smaller than 2 years. In Table 5, the largest time value smaller than 2 is 1.889, and the corresponding OS 0 (t) value is 0.791. Accordingly, the patient&#39;s probability of 2 year overall survival is P(PFS)=0.791 (exp(0.389)) =0.791 1.4476 =0.707 or 70.7%. 
     Example 4 
     This example demonstrates the biological basis for DLBCL prognostic signatures. 
     Unless otherwise indicated, cohorts and methods of gene expression analysis are described in Examples 1 and 2. Furthermore, cell suspensions from three biopsies were separated by flow cytometry into a CD19+ malignant subpopulation and a CD19− non-malignant subpopulation. Gene expression profiling was performed following two rounds of linear amplification from total RNA (Dave et al.,  N. Engl. J. Med.,  351: 2159-69 (2004)). After MAS5.0 normalization, genes were selected that had a log 2 signal value greater than 7 in either the CD19+ or CD19− fractions in at least two of the sorted samples. 
     To assess whether the gene expression signatures in the final survival model of Example 2 were derived from the malignant lymphoma cells or from the host microenvironment, three DLBCL biopsy samples were fractionated into CD19+ malignant cells and CD19− non-malignant cells by flow sorting. Most germinal center B cell signature genes were more highly expressed in the malignant fraction, whereas genes from the stromal-1 and stromal-2 signatures were more highly expressed in the non-malignant stromal fraction ( FIG. 4A ), hence their name. Since these two signatures were synergistic in predicting survival, they were combined into a “stromal score” ( FIG. 3 ), high values of which were associated with adverse outcome. 
     The germinal center B cell signature relates to the distinction between the ABC and GCB DLBCL subtypes ( FIG. 3 ). By contrast, the genes defining the stromal-1 signature encodes components of the extracellular matrix, including fibronectin, osteonectin, various collagen and laminin isoforms, and the anti-angiogenic factor thrombospondin ( FIG. 3  and Table 1). This signature also encodes modifiers of collagen synthesis (LOXL1, SERPINH1), proteins that remodel the extracellular matrix (MMP2, MMP9, MMP14, PLAU, TIMP2), and CTGF, a secreted protein that can initiate fibrotic responses (Frazier et al.,  J. Invest. Dermatol.,  107(3): 404-11 (1996)). In addition, the stromal-1 signature includes genes characteristically expressed in cells of the monocytic lineage, such as CEBPA and CSF2RA. 
     The stromal-1 signature is significantly related to several previously curated gene expression signatures (Shaffer et al.,  Immunol. Rev.,  210: 67-85 (2006)) based on gene set enrichment analysis (Subramanian et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  102(43): 15545-50 (2005)). Two of these signatures include genes that are coordinately expressed in normal mesenchymal tissues but not in hematopoietic subsets, many of which encode extracellular matrix proteins (false discovery rate (FDR)&lt;0.001) ( FIGS. 4B and 11 ) (Su et al.,  Proc. Nat&#39;l. Acad. Sci. USA,  101: 6062-7 (2004)). Also enriched was a “monocyte” signature, comprised of genes that are more highly expressed in CD14+ blood monocytes than in B cells, T cells, or NK cells (FDR=0.014) ( FIG. 4B ). By contrast, a pan-T cell signature was not related to the stromal-1 signature ( FIG. 4B ). These findings suggest that high expression of the stromal-1 signature identifies tumors with vigorous extracellular matrix deposition and infiltration by cells in the monocytic lineage. 
     In this regard, the stromal-1 signature gene product fibronectin was prominently localized by immunohistochemistry to fibrous strands running between the malignant cells in DLBCL biopsy samples, in keeping with its role in extracellular matrix formation. By contrast, the protein products of three other stromal-1 genes—MMP9, SPARC, and CTGF—were localized primarily in histiocytic cells that infiltrated the DLBCL biopsies. By immunofluorescence, SPARC and CTGF colocalized with CD68, which is a marker for cells in the monocytic lineage. As expected for a stromal-1 gene product, SPARC protein levels were associated with favorable overall survival ( FIG. 5A ). 
     The stromal-1 signature includes genes that are coordinately expressed in many normal mesenchymal tissues, most of which encode proteins that form or modify the extracellular matrix. The localization of fibronectin to fibrous strands insinuated between the malignant lymphoma cells suggests that the stromal-1 signature reflects the fibrotic nature of many DLBCL tumors. This fibrotic reaction may be related to another stromal-1 signature component, CTGF, which participates in many fibrotic responses and diseases, and promotes tumor growth and metastasis of epithelial cancers (Shi-Wen et al.,  Cytokine Growth Factor Rev.,  19: 133-44 (2008)). 
     The foregoing results also indicate that the stromal-1 signature reflects a monocyte-rich host reaction to the lymphoma that is associated with the abundant deposition of extracellular matrix. Tumors with high expression of the stromal-1 signature were infiltrated by cells of the myeloid lineage, which include cells that have been implicated in the pathogenesis of epithelial cancers, including tumor-associated macrophages, myeloid-derived suppressor cells, and Tie2-expressing monocytes (reviewed in Wels et al.,  Genes Dev.,  22: 559-74 (2008)). In animal models, these myeloid lineage cells promote tumor cell invasion by secreting matrix metalloproteinases such as MMP9, suppress T cell immune responses, and initiate angiogenesis. 
     Several stromal-2 signature genes encode well-known markers of endothelial cells. These include von-Willebrand factor (VWF) and CD31 (PECAMI), as well as other genes specifically expressed in endothelium such as EGFL7, MMRN2, GPR116, and SPARCL (Table 1). This signature also includes genes encoding key regulators of angiogenesis, such as, for example, KDR (VEGF receptor-2); Grb10, which mediates KDR signaling; integrin alpha 9, which enhances VEGF signaling; TEK, the receptor tyrosine kinase for the cytokine angiopoietin; ROBO4, an endothelial-specific molecular guidance molecule that regulates angiogenesis; and ERG, a transcription factor required for endothelial tube formation. The stromal-2 signature genes CAV1, CAV2, and EHD2 encode components of caveolae, which are specialized plasma membrane structures that are abundant in endothelial cells and required for angiogenesis (Frank et al.,  Arterioscler. Thromb. Vasc. Biol.,  23: 1161-8 (2003); Woodman et al.,  Am. J. Pathol.,  162: 2059-68 (2003)). Although the stromal-2 signature includes a large number of genes expressed in endothelial cells, other genes are expressed exclusively in adipocytes, including ADIPOQ, FABP4, RBP4, and PLIN. 
     Quantitative tests were done to determine whether expression of the stromal-2 signature relative to the stromal-1 signature (i.e., high stromal score) is related to high tumor blood vessel density, given the connection between many stromal-2 signature genes and angiogenesis. More specifically, the stromal-1 signature averages were subtracted from the stromal-2 signature average to thereby obtain a stromal score for each biopsy. Tests showed a quantitative measure of blood vessel density correlated significantly with the stromal score (r=0.483, p=0.019) (see  FIGS. 5B and 5C ), such that higher blood vessel densities correlated with higher stromal scores. 
     Thus, the stromal-1 and stromal-2 gene expression signatures reflect the character of the non-malignant cells in DLBCL tumors, and the stromal-2 signature may represent an “angiogenic switch” in which the progression of a hyperplastic lesion to a fully malignant tumor is accompanied by new blood vessel formation (Hanahan et al.,  Cell,  86: 353-64 (1996)). DLBCL tumors with high relative expression of the stomal-2 signature were associated with increased tumor blood vessel density and adverse survival. Significant macrophage infiltration in some DLBCL tumors may predispose to angiogenesis since, in experimental models, tumor-associated macrophages accumulate prior to the angiogenic switch and are required for the switch to occur (Lin et al.,  Cancer Res.,  66: 11238-46 (2006)). Additionally, CXCL12 (SDF-1), a stromal-2 signature component, is a chemokine secreted either by fibroblasts or endothelial cells that can promote angiogenesis by recruiting CXCR4+ endothelial precursor cells from the bone marrow (Orimo et al.,  Cell,  121: 335-48 (2005)). Moreover, an antagonist of angiogenesis, thrombospondin-2 (Kazerounian et al.,  Cell Mol. Life Sci.,  65: 700-12 (2008)), is a stromal-1 signature component, which may explain why tumors with low relative expression of this signature had an elevated blood vessel density. Furthermore, the expression of adipocyte-associated genes in DLBCL tumors with high stromal-2 signature expression may play a role in angiogenesis since some cells in adipose tissue may have the potential to differentiate into endothelial cells (Planat-Benard et al.,  Circulation,  109: 656-63 (2004)). Alternatively, the expression of adipose-associated genes may reflect the recruitment of bone marrow-derived mesenchymal stem cells, which home efficiently to tumors (Karnoub et al.,  Nature,  449: 557-63 (2007)) and can stabilize newly formed blood vessels (Au et al.,  Blood,  111: 4551-4558 (2008)). 
     The foregoing results indicate that the stromal-1 and stromal-2 gene signatures can be used to generate a stromal score that correlates with increased blood vessel density. Thus, the stromal score can be used to determine if a DLBCL patient is likely to benefit from administration of antiangiogenic therapy (alone, or in conjunction with another DLBCL therapeutic regimen). 
     All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. 
     The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. 
     Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.