Patent Publication Number: US-2011076283-A1

Title: Method for predicting and diagnosing brain tumor

Description:
FIELD OF THE INVENTION 
     The present invention relates to a method for predicting or diagnosing outcome of concomitant chemo-radiotherapy of a subject suffering from brain tumor. The present invention further relates to compositions and methods for treatment or prevention of tumor resistance in a subject suffering from a brain tumor and to a kit useful for predicting or diagnosing the tumor resistance in a subject treated with concomitant chemo-radiotherapy. 
     BACKGROUND OF THE INVENTION 
     Radiotherapy, chemotherapy, or a combination thereof are used to treat human tumors. In glioblastoma, introduction of combined chemo-radiotherapy of concomitant and adjuvant temozolomide (TMZ) and radiotherapy (TMZ/RT→TMZ) has allowed to significantly prolong survival (Stupp et al., 2005), in particular in patients with an epigenetically silenced O-6-methylguanine-DNA methyltransferase (MGMT) DNA repair gene (Hegi et al., 2005). However, outcome remains unsatisfactory and ongoing clinical trials explore modulation of MGMT or the addition of targeted agents. Recognizing molecular tumor signatures of underlying biological processes associated with resistance in patients treated with this new “standard therapy” will allow the identification of potential targets for improvement of therapy and the development of biomarkers for patient selection. 
     Several gene expression signatures associated with resistance to therapy were identified. Tumor resistance was associated with clustered genes dominated by HOX genes; and with two clusters G25 and G13 reflecting amplification driven overexpression of proto-oncogenes, EGFR on chromosome 7, and CDK4 &amp; MDM2 on chromosome 12, respectively. An additional cluster, G18 associated with brain physiology was correlated with resistance. Good prognosis was associated with clusters reflecting tumor-host interaction-related features comprising tumor stroma, characterized by markers for tumor blood vessels and myeloid lineage markers/cell adhesion, G7 and G14, and innate immune response G24. Most interestingly the cluster dominated by HOX genes was reminescent of a stem cell-related “self-renewal signature”. HOX gene expression is essential for axis determination during embryogenesis. Studies have reported deregulated HOX gene expression (defined as expression of normal HOX genes in a wrong cellular context) in a variety of cancers as shown in in vitro and in vivo mouse models (Abate-Shen, 2002). Similarly, in glioma, increased expression of HOX genes, as compared to normal brain, has been reported from astrocytoma II/III and glioblatoma (Abdel-Fattah et al., 2006). However, no associations with outcome or response to therapy have been reported, nor has a functional role of the HOX genes in glioma development been established. 
     These molecular signatures will be useful for patient stratification for specific therapies. The associations with outcome underline the need for development of multimodality treatments targeting not only the tumour cells, but including strategies aimed at the glioma stem-like cell compartment (identified by high HOX gene expression), and interfering with tumor host interaction that provides the specialized microenvironment relevant for the maintenance of tumour stem-like cells (the stem-cell niche). Better outcome was associated with gene clusters characterizing features of tumour host interaction including tumour vascularization and cell adhesion (G07, G14), and innate immune response. The positive association of high expression of tumour blood vessel markers (G07) with outcome may reflect improved perfusion of the active therapeutic drug. This signature may be of further interest for therapies aimed at targeting angiogenesis that are thought to improve blood perfusion of the tumors transiently. 
     Thus there is a profound need to develop an effective predictive method for identifying resistance to concomitant chemo-radiotherapy of a subject suffering from brain tumor and effective methods and compositions for treatment or prevention of this condition. The main problem is that to date, no efficient methods or strategies have been developed to overcome this problem and to identify patients benefiting from therapies. 
     SUMMARY OF THE INVENTION 
     This object has been achieved by providing a method for predicting or diagnosing outcome of concomitant chemo-radiotherapy of a subject suffering from brain tumor comprising: 
     (a) obtaining a biological sample from said subject,
 
(b) measuring the expression of gene clusters associated with tumor resistance to the concomitant chemo-radiotherapy treatment wherein said gene clusters are selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, G07 genes and G14 genes, biologically active fragment thereof and/or combinations thereof.
 
(c) comparing the expression level of said gene clusters to threshold values, wherein the high expression of HOX genes, G13 genes, G18 genes and G25 genes indicate high risk for brain tumor resistance to the concomitant chemo-radiotherapy treatment whereas the expression of G07 genes and G14 genes indicate better outcome to the concomitant chemo-radiotherapy treatment, and optionally evaluating the medical prognosis of said subject based on the comparison of step (c), and/or adapting the treatment of said subject.
 
     A further object of the present invention is to provide a kit useful for predicting or diagnosing the tumor resistance in a subject treated with concomitant chemo-radiotherapy, said kit comprises a set of primers, probes or antibodies specific for one or more genes selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, G07 genes and G14 genes, biologically active fragment thereof and/or combinations thereof. 
     Another object of the invention is the use of modulators of expression of at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof in the preparation of a medicament for the treatment or prevention of tumor resistance in a subject suffering from a brain tumor, wherein said modulators are inhibitors. 
     Further object of the invention is the use of modulators of the biological activity of a protein encoded by at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof in the preparation of a medicament for treatment or prevention of tumor resistance in a subject suffering from a brain tumor, wherein said modulators are inhibitors or competitors. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1 . Sample Dendrogram S1(G1) and Gene Distance Matrix (G1) by Coupled Two-Way Clustering (CTWC). 
       (A) Sample dendrogram S1(G1) emerging from clustering all 84 samples S1 with all genes G1. Stable sample clusters S2 to S6 emerge. Clinical information: age at diagnosis, green&lt;50 years; brown&gt;50 years; overall survival, OS, in months, green&lt;9; red 9-18; pink&gt;18; MGMT methylation status, grey, methylated; black, unmethylated; white unknown; gender, red, female; sample Id#, sample identification number, non tumoral brain tissue, yellow; recurrent glioblastoma, black; color code tumor pairs from same patient, black only recurrent glioblastoma. (see URL in Methods to view gene dendrogram and entire CTWC analysis)
 
(B): The distance matrix of all filtered genes (G1) (Euclidian distance) heatmap; blue, short distance (more similar), red, large distance. The “distance” ranges from 0 (corresponding to Pearson correlation=1, i.e. full similarity of the two expression profiles) to 2 (corresponding to anti-correlated profiles, Pearson=−1). Zero correlation, orange. Annotation is based on gene dendrogram G1(S1) (not shown). The distance matrix visualizes relationships between clusters as indicated by lines and arrows: e.g. G7 is in the center of a “supercluster”, reflecting close relationship with G9, G12, G14 and G2. In addition G7 is related to G29, but not G23 or G21.
 
(C): Respective distance matrices for two published data-sets with 48 and 54 glioblastoma (Freije et al., 2004; Phillips et al., 2006), comprising the common probe-sets (3649) and ordered according to the matrix in  FIG. 1B . All 3 data-sets appear very similar, particularly visible for the largest clusters annotated in  FIG. 1B .
 
         FIG. 2 . Relation of Glioblastoma Derived Hox Gene Signature with Survival 
       (A) Stable cluster G98 was found by clustering all genes G1 with samples clustered in S4 (69 glioblastoma), red, relative overexpression; blue relative underexpression.
 
(B) Glioblastoma-derived neurospheres (40×) cultured under stem cell conditions exhibit strong nuclear staining for HOXA10 and express CD133 as determined by immunohistochemistry. Representative neurospheres from two glioblastoma are shown.
 
(C) Kaplan-Meier survival estimates of the 42 patients treated with TMZ/RT→TMZ separated into high versus low expressors of G98 genes, High HOX, Low HOX (dichotomized according to CTWC sample dendrogram). The p-value of the log-rank test is shown for the two groups, stratified by the MGMT methylation status, M-MGMT, methylated MGMT; U-MGMT, unmethylated MGMT.
 
         FIG. 3 . HOXA10 Expression and Overall Survival in Independent Patient Cohort. 
       (A) HOXA10 expression determined by immunohistochemistry on TMA. Diameter of tissues in upper panel: 0.6 mm. First panel, high nuclear expression; second, focal high nuclear expression; third, no expression.
 
(B) Kaplan-Meier survival estimates of 39 patients randomized to TMZ/RT→TMZ and 37 patients randomized to RT, separated into high versus low expressors of HOXA10 as determined by immunohistochemistry on TMA.
 
         FIG. 4 . Association of EGFR Expression with Survival. 
       Kaplan-Meier curves of the 42 patients in the TMZ/RT→TMZ cohort divided between low and high expression of EGFR (probeset 201983_s_at, dichotomized according to a Gaussian mixture model). The p-value from log-rank test is shown for two groups defined by EGFR expression and stratified according to the MGMT methylation status. M-MGMT, methylated MGMT; U-MGMT, unmethylated MGMT. 
         FIG. 5 . PLS model for survival Cluster X-weights were obtained by averaging the X-weights of their constituent genes. The clusters are numbered according to the legend and the description in Table 1. Age and MGMT methylation-status were used as covariates. Clusters of genes with X-weights that are nearest to the PLS factors, represented by the axes (PLS factor 1 and 2), and the farthest from the center of the plane contribute most to the PLS regression. The first two factors shown explain 66% of the survival outcome variations. Clusters of genes grouped in the upper and right side of the plane have a positive association with shorter survival (i.e. higher hazards), while those in the lower and left side are positively associated with longer survival (i.e. lower hazards). 
         FIG. 6 . Correlation of G98 expression and survival in external datasets. High expression of the selfrenewal cluster G98 is significantly associated with worse outcome in two independent datasets comprising a total of 146 malignant glioma (P=0.007, hazard ratio: 1.46, 95% Confidence Interval: 1.11 to 1.92) (model adjusted for tumor grade WHO grade III and IV; age, and stratified for the dataset, Nelson; Aldape). The forest plots visualize the relationship between expression of G98 and outcome in the two datasets separated for tumor grade. The hazard ratio for GBM (WHO grade IV) is 1.29 (95% CI 0.97 to 1.72, P=0.09) (left panel). A hazard ratio of 3.35 (95% CI 1.39 to 8.08; P=0.007) is observed for the subset of anaplastic glioma (WHO grade III) (right panel) 
         FIG. 7 . Box plot for expression of G98 in grade III and grade IV glioma of external datasets. G98 expression significantly differentiates anaplastic glioma (WHO grade III) from GBM (WHO grade IV). GBM exhibit significantly higher expression of G98 in both external data sets (Wilcoxon rank sum test with continuity correction, Nelson, P&lt;0.001; Aldape, P=0.002). 
         FIG. 8 . HOX-signature and Self-renewal. Genes in the HOX gene cluster G 98 are significantly (P=0.008) enriched in the mouse expression data among genes differentiating mouse hematopoetic cell populations into two classes, A) self renewal-assocaited samples: granulocyte macrophage progenitor-derived leukemic cells (L-GMP), and hematopoietic stem cells (HSC); and B) non self renewal associated samples: common myeloid progenitors (CMP), granulocyte macrophage progenitors (GMP), and megakaryocyte erythrocyte progenitors (MEP). Heat map: dark grey=up regulated; light grey=down regulated, in comparison to the median expression value. 
         FIG. 9 . Array-CGH data of the HOX gene region. aCGH data for the chromosomal region around the HOX gene cluster on chromosome 7. Every row is a marker, ordered by chromosomal location. Every column is a sample (n=60), ordered by the copy number of BAC GS1-213H12 (bacterial artificial chromosome) using SPIN software. The HOXA gene cluster resides between markers GS1-213H12 and CTB-23D 2 O that appear to be amplified more frequently and more strongly than the neighboring markers. 
         FIG. 10 . Expression of CD163 in GBM Immunohistochemistry for CD163 (Novocastra; NCL-163; dilution 1:800) on representative paraffin-embedded GBM. Diameter of tissues in upper panel is 0.6 mm. CD163 is a marker for M2-polarized macrophages. 
         FIG. 11 . Expression of HOXA10 &amp; 9 RNA in Glioma. FB, fetal brain; NB, normal brain 
         FIG. 12 . Promoter Methylation of HOXA9 &amp; 10 increases with Tumor Malignancy in Glioma. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. 
     As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention. 
     The term “comprise” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. 
     As used in the specification and claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. The term “a protein” includes a plurality of proteins. 
     As used herein, the terms “peptide”, “protein”, “polypeptide”, “polypeptidic” and “peptidic” are used interchangeably to designate a series of amino acid residues connected to the other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues. 
     Glioblastoma are notorious for resistance to therapy which has been attributed to DNA repair proficiency, a multitude of deregulated molecular pathways, and more recently to the particular biological behavior of tumor stem-like cells. In the present invention the Applicants identified molecular profiles specific for treatment resistance to the current standard of care of concomitant chemo-radiotherapy with the alkylating agent temozolomide. 
     Recent concepts for cancer development suggest that a minority population of cancer stem-like cells may determine the biological behavior of tumors, including response to therapy. Failure to cure cancer has been attributed to the fact that therapies are aimed at the tumor bulk without significantly harming tumor stem-like cells (Reya et al., 2001), supported by experimental evidence in a respective mouse model showing that this glioblastoma subpopulation of cells is more resistant to radiotherapy (Bao et al., 2006). Facilitated by markers differentiating stem-cells and progenitors of the different lineages, the origin of leukemic stem-cells has been traced back to hematopoietic stem-cells as well as progenitor populations that have acquired “self-renewal” properties (Krivtsov et al., 2006). In contrast, the origin and concept of glioma stem-like cells remains to be fully elucidated. CD133 +  has been postulated to be a glioma stem-cell marker, as this subpopulation of glioma-derived cells seems to have a higher potential to generate and maintain tumors in vivo (Bao et al., 2006). 
     The Applicants have identified several biological processes associated with resistance or responsiveness to combined chemo-radiotherapy that provide important information guiding novel treatment strategies and aiming at individualized therapy. Intriguingly, an expression signature associated with resistance shows high similarity with a stem cell-related “self-renewal” signature (Krivtsov et al., 2006). 
     The Applicants provide first clinical evidence for the implication of a “glioma stem-cell” or “self-renewal” phenotype in treatment resistance of glioblastoma. Biological mechanisms identified here to be relevant for resistance will guide future targeted therapies, and respective marker development for individualized treatment and patient selection. 
     Gene expression signatures relevant for treatment resistance to TMZ/RT→TMZ have been identified in a prospectively treated population of glioblastoma patients. While epigenetic inactivation of the MGMT gene promoter remained the most prominent predictive factor, expression signatures allowed identification of patient sub-groups who may benefit from specific additional therapies targeting particular mechanisms of resistance. 
     As an independent predictive factor of resistance the Applicants have identified a HOX-dominated gene cluster, evocative of a “self-renewal signature”. Strong HOXA10 expression of glioblastoma derived neurospheres is in line with a role of HOX-genes in the glioma stem-like cell compartment. These findings provide the first clinical evidence for the relevance of a stem-like cell phenotype in treatment resistance of glioblastoma. 
     A “gene cluster” refers to a set of two or more genes that serve to encode for the same or similar products. 
     In leukemia expression of translocation-related fusion proteins lead to MLL-mediated chromatin remodeling associated with re-expression of HOX-genes (Dorrance et al., 2006). In glioblastoma, however, such fusion proteins have not been described, and no indications from the present data-set link MLL-expression with the “self-renewal signature”. The Applicant&#39;s provide evidence that the HOX-dominated gene signature emerges with malignant progression to glioblastoma, and may be acquired in some glioblastoma by low level amplification, the latter supporting the notion that gliomas may also arise from progenitors, in agreement with mouse models (Bachoo et al., 2002). The identification of GADD45G as part of the HOX-signature may provide further evidence for an enhanced DNA repair potential that recently has been associated with radiation resistance of glioma stem cells (Bao et al., 2006). 
     These molecular and clinical data underscore the importance of the self-renewal phenotype which could be explored as a potential treatment target (Stupp and Hegi, 2007). First efforts blunting glioma stem-cell-related self-renewal properties of tumors suggest that strategies forcing differentiation, e.g. mediated by cytokines such as BMP4, may be promising (Piccirillo et al., 2006). 
     Targeting resistance to TMZ/RT→TMZ associated with overexpression of the EGFR gene is of particular clinical interest, since this alteration affects a large proportion of patients. CDK4 and MDM2 genes, both proto-oncogenes showed amplification-mediated overexpression, are identified in the present invention as associated with worse outcome. 
     Surprisingly, good prognosis was associated with increased expression of a signature for tumor endothelium markers. This signature may predict improved cytotoxic activity by means of better perfusion of the tumor with the chemotherapy agent TMZ. This is in accordance with the concept suggesting that anti-angiogenic agents may temporarily lead to “normalization” of aberrant tumor vasculature resulting in more efficient delivery of drugs and oxygen to the tumor (Batchelor et al., 2007). In a recent trial addition of the anti-angiogenic integrin-inhibitor cilengitide appears to confer increased anti-tumor activity in conjunction with TMZ/RT→TMZ in patients with a methylated MGMT gene promoter (Stupp et al., 2007). 
     Another interesting insight of the present invention suggests infiltration of M2-polarized macrophages into the tumors. The altered capacity of these glioma-infiltrating macrophages to induce effective anti-tumor T-cell response may obstruct therapeutic strategies aimed at boosting adaptive immunity against the tumor. M2-polarization is driven by tumor-derived and T-cell-derived cytokines (Mantovani et al., 2002), consistent with the well-known expression of the immunosuppressive cytokines TGF-beta and Interleukin 10 in malignant glioma (Kjellman et al., 2000). Thus, for effective immunotherapy/vaccination full resection of the tumor may be required to remove the microenvironment conferring immunosuppression and tolerance. 
     The gene signatures identified in the present invention is associated with outcome underline the need for development of multimodality treatments targeting not only the tumor cells, but including strategies aimed at the glioma stem-like cell compartment, and interfering with tumor host interaction that provides the specialized microenvironment relevant for the maintenance of tumor stem-like cells (the stem-cell niche), angiogenesis, and immune response. The present invention is useful to guide a rational choice of agents, targets, trial design, and appropriate patient selection, incorporating biomarkers defining mechanisms of response and resistance. 
     Epigentic silencing of HOX-genes by promoter methylation increases during malignant progression of glioma. Prognostic marker in the tissue and body-fluids such as cerebrospinal fluid (CSF) and blood. 
     Progression of gliomas to glioblastoma (WHO grade IV) is associated with increasing expression of HOX genes (eg HOX genes in cluster G98/G28). 
     Investigation of HOXA10 and HOXA9 in glioma revealed epigenetic promoter deregulation associated with tumor malignancy, reflected by the presence of respective hypermethylated gene promoter alleles in most GBM (12/17 and 13/17, respectively) in contrast to lower grade gliomas (2/11 and 3/10; Fisher exact test p=0.009 and p=0.02,  FIG. 11 ). In all tumors unmethylated alleles were also present. Tumors with methylated promoters showed HOXA10 and HOXA9 expression, while, normal brain showed no methylation and no expression, like most low grade gliomas ( FIG. 12 ). 
     The high frequency of HOXA10 and 9 promoter methylation in glioblastoma makes these very good prognostic markers in the tissue but also for detection in cerebrospinal fluid (CSF) or blood. In the CSF and blood they have not only a prognostic value on their own, prediction of high grade glioma, but also may serve as marker for tumor derived DNA. The promoter methylation can be detected by many different technologies including MSP, pyrosequencing, MS etc. 
     Thus, the present invention relates to a method for predicting or diagnosing outcome of concomitant chemo-radiotherapy of a subject suffering from brain tumor comprising: 
     (a) obtaining a biological sample from said subject,
 
(b) measuring the expression of gene clusters associated with tumor resistance to the concomitant chemo-radiotherapy treatment wherein said gene clusters are selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, G07 genes and G14 genes, biologically active fragment thereof and/or combinations thereof.
 
(c) comparing the expression level of said gene clusters to threshold value, wherein the high expression of HOX genes, G13 genes, G18 genes and G25 genes indicate high risk for brain tumor resistance to the concomitant chemo-radiotherapy treatment whereas the expression of G07 genes and G14 genes indicate better outcome to the concomitant chemo-radiotherapy treatment, and optionally evaluating the medical prognosis of said subject based on the comparison of step (c), and/or adapting the treatment of said subject.
 
     The term “radiotherapy” refers to the use of ionizing radiation as part of cancer treatment to control malignant cells. It is also common to combine radiotherapy with surgery, chemotherapy, hormone therapy or combinations thereof. Most common cancer types can be treated with radiotherapy in some way. The precise treatment intent (curative, adjuvant, neoadjuvant, or palliative) will depend on the tumor type, location, and stage, as well as the general health of the patient. 
     The term “chemotherapy” generally refers to a treatment of a cancer using specific chemotherapeutic/chemical agents. A chemotherapeutic agent refers to a pharmaceutical agent generally used for treating cancer. The chemotherapeutic agents for treating cancer include, for example, cisplatin, carboplatin, etoposide, vincristine, cyclophosphamide, doxorubicin, ifosfamide, paclitaxel, gemcitabine, docetaxel, and irinotecan and platinum-based anti-cancer agents, including cisplatin and carboplatin. Other chemotherapy classes comprise tyrosine kinase inhibitors such as gefitinib, imatinib; farnesyl transferase inhibitors including lonafarnib; inhibitors of mammalian targets of rapamycin (mTOR) such as evereolimus; angiogenesis inhibitors including bevacizumab, sunitibid and cilengitide; inhibitors of PKC; PI3K and AKT. More specifically, the chemotherapeutic agents of the present invention include alkylating agents such as Temozolomide or carmustine. 
     The term “concomitant chemo-radiotherapy” is used when these two treatments (chemotherapy and radiotherapy) are given either at the same time, or almost at the same time, for instance one after the other, or on the same day, etc. 
     According to the present invention, the preferred agent for chemotherapy is temozolomide (TMZ). 
     The term “adapting the treatment” generally refers to the choice of a treatment among different options, based on the specificities of the disease, concomitant pathologies or patient conditions, or the switch from one treatment to another in the course of the therapy because of the non-response, progression or resistance of the disease to the initial treatment, with the intent to offer to the patients the beast treatment for his diseases under the given circumstances. 
     The biological sample, used in the method of the invention, is a biopsy of brain tumor. Preferably, the biological sample is a glioblastoma sample. 
     In the method of the present invention, the subject is a mammal and preferably a human. 
     As used herein the terms “subject” or “patient” are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject is a subject in need of treatment. However, in other embodiments, the subject can be a normal subject. 
     In the method of the present invention the HOX gene cluster includes one or more genes selected from the group comprising GADD45G, SCAP2, HOXD4, HOXC6, HOXA9, HOXA10, HOXA5, HOXA2, SCAP2, LOC400043, LOC375295, HOXD10, HOXD8, HOXA3, HOXA7, HOXD10, FLJ41747, PROM1, TSHZ2, and FAM110C. Preferably HOX genes are HOXA9 and HOXA10. 
     In the method of the present invention the G13 gene cluster includes one or more genes selected from the group comprising B4GALNT1, AVIL, OS9, CDH1, CDK4, TSPAN31, METTL1, MDM2, CYP27B1, CPM, TSFM, FAM119B, SLC26A10, NUP107, KIAA1267, MGC5370, MARCH9, XRCC6BP1, DTX3, and RGS8. Preferably G13 genes are CDK4 and MDM2 (see table 11). 
     The expression level of said gene clusters is then compared to threshold value, said “threshold value” refers to, e.g. the expression level of all RNA transcripts or their expression products in said sample or of a reference set of RNA transcripts or their expression products in said sample. Usually, a high expression of HOX genes, G13 genes, G18 genes and G25 genes indicate high risk for brain tumor resistance to the concomitant chemo-radiotherapy treatment whereas the expression of G07 genes and G14 genes indicate better outcome to the concomitant chemo-radiotherapy treatment, and optionally evaluating the medical prognosis of said subject based on the comparison of expression level of said gene clusters, and/or adapting the treatment of said subject. 
     The term “prognosis” is recognized in the art and encompasses predictions about the likely course of disease or disease progression, particularly with respect to likelihood of disease remission, disease relapse, tumor recurrence, metastasis, and death. 
     In the method of the present invention the G18 gene cluster includes one or more genes selected from the group comprising SLC1A3, ITPKB, MAOB, F3, BBOX1, DTNA, NDP, NR2E1, P2RY1, CA2, SLC7A11, AQP4, MLC1, CENTD1, SLC25A18, ITGB8, PAX6 and FLJ25530. Preferably G18 genes are AQP1 and AQP4. 
     In the method of the present invention the G25 gene cluster includes one or more genes selected from the group comprising EGFR, SOCS2, SEC61G, EYA2, SHOX2, EMILIN3, MASP1, FOXO1A, LHFP, and PDZD2. Preferably G25 gene is EGFR. 
     In the method of the present invention the G07 gene cluster includes one or more genes selected from the group comprising COL1A1, KDELR2, LAMC1, COL6A3, LAMB1, LUM, COL3A1, NID1, VWF, LAMA4, MGP, SEC24D, COL1A2, PCOLCE, FMOD, FBN1, CD93, ADAM12, LOXL2, COL5A1, IGFBP6, KDELR3, TPM2, NID2, EDNRA, CDH5, LTBP2, ENPEP, SRPX2, ANGPT2, SERPINH1, PDLIM1, COL6A2, MXRA5, FN1, ANGPT2, COL13A1, FN1, COL4A2, COL4A1, NRP1, MYO1B, OLFML2B, SNAI2, PLXDC1, LXN, ELTD1 NOX4, COL5A2, ETS1, CTHRC1, MGC4677///L00541471, PELO, FAM20A, LOC493869, and GJA7. 
     In the method of the present invention the G14 gene cluster includes one or more genes selected from the group comprising ALDH1A3, MME, THBS4, BMP5, MEOX1, COMP, GAS2, SEPT6///N-PAC, SOSTDC1, OLFML1, RP6-213H19.1, CYTL1, PRR16, TNMD, FNDC1, GLT8D2, CDC42EP5, SCARA5, COL12A1, DNM3, HMCN1 and MKX. Preferably G14 genes are PRR16, MEOX1, MKX and BMP5. 
     Comparing the expression level of said gene clusters to threshold value, wherein the high expression of HOX genes, G13 genes, G18 genes and G25 genes indicate high risk for brain tumor resistance to the concomitant chemo-radiotherapy treatment whereas the expression of G07 genes and G14 genes indicate better outcome to the concomitant chemo-radiotherapy treatment, and optionally evaluating the medical prognosis of said subject based on the comparison of step (c), and/or adapting the treatment of said subject. 
     The Cluster Indexes (CI) are defined as follows (the “Clusters”, Gxx: gene cluster G07, G13, G14, G18, G25, HOX genes, as defined in the Tables): 
         Gxx CI=log 2  [( CTE   1   +Gxx  Cluster Metagene Score)/( CTE   2 +Reference Metagene Score)]+ CTE   3    
     The Cluster metagene score is a weighted average of the expression values of the genes in the Cluster (see, respective Tables of clusters) measured within the tumor biopsy. 
     
       
         
           
             
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         n=2 to number of genes in the Cluster   “GxxCuster Gene,” represents the expression value of each gene in the cluster.   ks i  defines the importance of the corresponding gene in the calculation of the weighted average of the Cluster Metagene Score. The variable ks i  may take any positive real value within the range of zero (inclusive) and 1000 times the maximal expression value of the gene in the Cluster included in the calculation of the Cluster Metagene score.       

     Preferably the expression value of more than 2 genes in the Cluster are used to calculate the Cluster Metagene Score. 
     The purpose of the variable ks i  is to adjust (or correct) for the difference in expression magnitude between genes in the Cluster and therefore will make these expression values more similar to all other genes in the Cluster included in the calculation of the Cluster Metagene Score. 
     The variable CTE1 may take any real value within the range of plus/minus 1000 times the average of the Cluster Metagene Score. The purpose of the CTE1 variable is to adjust for differences in efficiency in extracting the mRNA of genes in the Cluster from the tumor sample relative to the reference genes. 
     The reference metagene score is a weighted average of the expression values of the reference genes (see Table of reference genes) measured within the tumor biopsy. 
     
       
         
           
             
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         n=2 to 6   “Reference Gene t ” represents the expression value of each reference gene.       

     kr t  defines the importance of the corresponding reference gene in the calculation of the weighted average of the Reference Metagene Score. The variable kr t  may take any positive real value within the range of zero (inclusive) and 1000 times the maximal expression value of the reference gene included in the calculation the Reference Metagene Score. 
     The purpose of the variable kr t  is to adjust (or correct) for the difference in expression magnitude between reference genes and therefore will make these expression values more similar to all other reference genes included in the calculation of the Reference Metagene Score. 
     The variable CTE2 may take any real value within the range of plus/minus 1000 times the average of the reference metagene score. The purpose of the CTE2 variable is to adjust for differences in efficiency in extracting the mRNA of reference genes from the tumor sample relative to the genes in the Cluster. 
     The purpose of the variable CT3 is to adjust for systematic bias due to experimental measurements. 
     A tumor sample is considered as being high expressor if the score CI is greater than the threshold TH1 (i.e. CI&gt;TH1), which is indicative of resistance to chemoradiotherapy true for HOX genes, G13, G18 and G25; but of sensitivity to chemoradiotherapy true for clusters G7 and G14. 
     A tumor sample is considered as being low expressor if the score CI is lower than the threshold TH2 (i.e. CI&lt;TH2), which is indicative of sensitivity to chemoradiotherapy true for HOX genes, G13, G18 and G25; but of resistance to chemoradiotherapy true for clusters G7 and G14. 
     The variables TH1 and TH2 can take any real value between −50 and +50. 
     The purpose TH1 constant is to adjust for the desired sensitivity and specificity in declaring a tumor sample as having a high Cluster Score. As the threshold TH1 increases, there will be an increase in the true positive rate when classifying a tumour sample as being high expressor. 
     The purpose of the TH2 constant is to adjust for the desired sensitivity and specificity in declaring a tumour sample as being low expressor. As the value of TH2 decreases, the higher will be the true positive rate of classifying a sample as being low expressor. 
     The use of both constant brings the advantage of controlling specificity and selectivity of samples being low and high expressor and thus leaving a security margin for samples having “dubious” (i.e. ambiguous) values. 
     According to the method of the present invention, the measuring of the expression of genes associated with tumor resistance to concomitant chemo-radiotherapy treatment is obtained by a method selected from the group consisting of: 
     (a) detecting RNA levels of said gene, and/or
 
(b) detecting a protein encoded by said gene, and/or
 
(c) detecting a biological activity of a protein encoded by said gene.
 
     The detecting of RNA levels is obtained through Microarray hybridization, real-time polymerase chain reaction, Northern blot, In Situ Hybridization, sequencing-based methods, quantitative reverse transcription polymerase-chain reaction or RNAse protection assay. 
     The detecting of protein levels is obtained through Western blot, immunoprecipitation, immunohistochemistry, ELISA, Radio Immuno Assay, proteomics methods, or quantitative immunostaining methods. 
     The present invention further relates to a method for predicting or diagnosing the brain tumor in a subject, comprising:
         (a) obtaining a biological sample from said subject,   (b) analyzing the epigenetic changes such as promoter methylation of HOXA10 and HOXA9 gene in glioblastoma, wherein the high frequency of HOXA10 and HOXA9 promoter methylation in glioblastoma is associated with tumor malignancy.       

     The said biological sample is body fluid, preferably cerebrospinal fluid (CSF) or blood. 
     The present invention also relates to a method for treatment or prevention of tumor resistance in a subject suffering from a brain tumor. The present invention encompasses the use of modulators of expression of at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, and G25 genes, biologically active fragment thereof and/or combinations thereof in the preparation of a medicament for the treatment or prevention of tumor resistance in a subject suffering from a brain tumor. 
     “Treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. Hence, the mammal to be treated herein may have been diagnosed as having the disorder or may be predisposed or susceptible to the disorder. 
     “Prevention” as used herein means that the administration of the modulator(s) as described results in a reduction in the likelihood that a subject at high risk for tumor resistance, relapse and/or metastatic progression after targeted anti-tumor therapy, radiotherapy, chemotherapy, or combination thereof will indeed develop said tumor resistance, relapse and/or metastatic progression. Preferably, in the context of the present invention, this phrase means that the administration of the modulator(s) results in the reduction of the likelihood or probability that a subject at risk for developing insulin-dependent diabetes will indeed develop tumor resistance, relapse and/or metastatic progression. 
     “Biologically active” means affecting any physical or biochemical properties of a living organism or biological process. Biologically Active Substance refers to any molecule or mixture or complex of molecules that exerts a biological effect in vitro and/or in vivo, including pharmaceuticals, drugs, proteins, peptides, polypeptides, hormones, vitamins, steroids, polyanions, nucleosides, nucleotides, nucleic acids (e.g. DNA or RNA), nucleotides, polynucleotides, etc. 
     “Fragments”, as referred to genes, are sequences sharing at least 40% nucleotides in length with the respective sequence of the gene. These sequences can be used as long as they exhibit the same biological properties as the native sequence from which they derive. Preferably these sequences share more than 70%, preferably more than 80%, in particular more than 90% nucleotides in length with the respective sequence from which it derives. 
     These fragments can be prepared by a variety of methods and techniques known in the art such as for example chemical synthesis. 
     In the present invention, said modulators of expression of at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, and G25 genes, biologically active fragment thereof and/or combinations thereof are preferably inhibitors, which comprise RNA antisense, said RNA antisense comprising a nucleotide sequence complementary to a coding sequence of at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     According to the present invention, the inhibitors of expression of at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, and G25 genes, biologically active fragment thereof and/or combinations thereof are also RNA interferents. 
     Furthermore, the inhibitors of expression of at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, and G25 genes, biologically active fragment thereof and/or combinations thereof comprise an antibody, or an immunologically active fragment thereof, that binds to a protein encoded by any gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     The present invention also relates to the use of modulators of the biological activity of a protein encoded by at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof in the preparation of a medicament for treatment or prevention of tumor resistance in a subject suffering from a brain tumor. 
     In the present invention, said modulators of the biological activity of a protein encoded by at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof are preferably inhibitors or competitors. 
     The inhibitor of the biological activity of a protein encoded by at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof is an antibody or immunologically fragment thereof that binds to a protein encoded by at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     The competitors are compounds able to disturb interaction between a protein and a receptor thereof, said protein being encoded by at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     In the context of the present invention, the RNA antisense reduces the expression of the specific target gene. For example, the RNA antisense can contain one or more nucleotides which are complementary to one or more gene sequences selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     The antisense nucleic acids (DNA or RNA) of the present invention act on cells producing the proteins encoded by genes associated with tumor resistance to the concomitant chemo-radiotherapy, by binding to the DNAs or mRNAs encoding the proteins, inhibiting their transcription or translation, promoting the degradation of the mRNAs, and inhibiting the expression of the proteins, thereby resulting in the inhibition of the protein function. 
     An antisense nucleic acid (DNA or RNA) of the present invention can be made into an external preparation, including a liniment or a poultice, by admixing it with a suitable base material which is inactive against the nucleic acid. 
     Also, as needed, the antisense nucleic acids of the present invention can be formulated into tablets, powders, granules, capsules, liposome capsules, injections, solutions, nose-drops and freeze-drying agents by adding excipients, isotonic agents, solubilizers, stabilizers, preservatives, pain-killers, and such. These can be prepared by following known methods. 
     The antisense nucleic acids of the present invention can be given to the patient by direct application onto the ailing site or by injection into a blood vessel so that it will reach the site of ailment. An antisense-mounting medium can also be used to increase durability and membrane-permeability. Examples include, but are not limited to, liposomes, poly-L-lysine, lipids, cholesterol, lipofectin or derivatives of these. The dosage of the inhibitory nucleic acid derivative of the present invention can be adjusted suitably according to the patient&#39;s condition and used in desired amounts. For example, a dose range of 0.1 to 100 mg/kg, preferably 0.1 to 50 mg/kg can be administered. 
     The antisense nucleic acids of the present invention inhibit the expression of a protein encoded by one or more genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof and are thereby useful for suppressing the biological activity of said protein. In addition, expression-inhibitors, comprising antisense nucleic acids of the present invention, are useful in that they can inhibit the biological activity of a protein of the present invention. 
     Usually, the antisense nucleic acids of the present invention include modified oligonucleotides. For example, thioated oligonucleotides can be used to confer nuclease resistance to an oligonucleotide. 
     Alternatively, the inhibitors of expression of said gene also comprise RNA interferents (interfering RNA or siRNA) compositions (i.e., a composition comprising one or more siRNA oligonucleotides). In the context of the present invention, the siRNA composition reduces the expression of one or more genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     Herein, the term “RNA interferent” or “siRNA” refers to a double stranded RNA molecule which prevents translation of a target mRNA. In the context of the present invention, the siRNA comprises a sense nucleic acid sequence and an anti-sense nucleic acid sequence against a high expression of one or more genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. The siRNA can be constructed fully synthetically and consisting of two complementary single stranded RNA or biosynthetically The siRNA is constructed such that a single transcript has both the sense and complementary antisense sequences from the target gene, (e.g. a single hairpin RNA or shRNA). Standard techniques for introducing siRNA into the cell can be used, including those in which DNA is a template from which RNA is transcribed. 
     Usually, an siRNA of one or more genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof, hybridizes to target mRNA and thereby decreases or inhibits production of the polypeptides encoded by the genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof by associating with the normally single-stranded mRNA transcript, thereby interfering with translation and thus, expression of the protein. Thus, siRNA molecules of the invention can be defined by their ability to hybridize specifically to mRNA or cDNA of one or more genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     In the context of the present invention, an siRNA is preferably less than 500, preferably less than 200, more preferably less than 100, even more preferably less than 50, or most preferably less than 25 nucleotides in length. More preferably an siRNA is about 19 to about 25 nucleotides in length. In order to enhance the inhibition activity of the siRNA, one or more uridine (“u”) nucleotides can be added to 3′ end of the antisense strand of the target sequence. The number of “u&#39;s” to be added is at least 2, generally 2 to 10, preferably 2 to 5. The added “u&#39;s” form a single strand at the 3′ end of the antisense strand of the siRNA. 
     An siRNA of one or more genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof, can be directly introduced into the cells in a form that is capable of binding to the mRNA transcripts. In these embodiments, the siRNA molecules of the invention are typically modified as described above for antisense molecules. Other modifications are also possible, for example, cholesterol-conjugated siRNAs have shown improved pharmacological properties. Song, et al, Nature Med. 9:347-51 (2003). Alternatively, a DNA encoding the siRNA can be carried in a vector. 
     The inhibitors of expression of said one or more genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof may also be an antibody, or an immunologically active fragment thereof, that binds to a protein encoded by any one gene selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     “Biologically active” means affecting any physical or biochemical properties of a living organism or biological process. Biologically Active Substance refers to any molecule or mixture or complex of molecules that exerts a biological effect in vitro and/or in vivo, including pharmaceuticals, drugs, proteins, peptides, polypeptides, hormones, vitamins, steroids, polyanions, nucleosides, nucleotides, nucleic acids (e.g. DNA or RNA), nucleotides, polynucleotides, etc. 
     Fragments are sequences sharing at least 40% amino acids in length with the respective sequence of the polypeptide. These sequences can be used as long as they exhibit the same biological properties as the native sequence from which they derive. Preferably these sequences share more than 70%, preferably more than 80%, in particular more than 90% amino acids in length with the respective sequence from which it derives. These fragments can be prepared by a variety of methods and techniques known in the art such as for example chemical synthesis. 
     A variant is a peptide having an amino acid sequence that differs to some extent from a native sequence peptide, that is an amino acid sequence that vary from the native sequence by conservative amino acid substitutions, whereby one or more amino acids are substituted by another with same characteristics and conformational roles. The amino acid sequence variants possess substitutions, deletions, side-chain modifications and/or insertions at certain positions within the amino acid sequence of the native amino acid sequence. Conservative amino acid substitutions are herein defined as exchanges within one of the following five groups: 
     I. Small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro, Gly
 
II. Polar, positively charged residues: His, Arg, Lys
 
III. Polar, negatively charged residues: and their amides: Asp, Asn, Glu, Gln
 
IV. Large, aromatic residues: Phe, Tyr, Trp
 
V. Large, aliphatic, nonpolar residues: Met, Leu, Ile, Val, Cys.
 
     It is to be understood that some non-conventional amino acids may also be suitable replacements for the naturally occurring amino acids. For example Lys residues may be substituted by ornithine, homoarginine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys and N,N,N-trimethyl-Lys. Lys residues can also be replaced with synthetic basic amino acids including, but not limited to, N-1-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4-piperinyl)-Ala, 2-[3-(2S)pyrrolininyl]-Gly and 2-[3-(2S) pyrrolininyl]-Ala. Tyr residues may be substituted with 4-methoxy tyrosine (MeY), meta-Tyr,ortho-Tyr, nor-Tyr,1251-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, and nitro-Tyr. 
     Tyr residues may also be substituted with the 3-hydroxyl or 2-hydroxyl isomers (meta-Tyr or ortho-Tyr, respectively) and corresponding O-sulpho- and O-phospho derivatives. Tyr residues can also be replaced with synthetic hydroxyl containing amino acids including, but not limited to 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr. 
     Aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains CnH2n+2 where n is a number from 1 up to and including 8. Examples of suitable conservative substitutions by non-conventional amino acids are given in WO02/064740. 
     Insertions encompass the addition of one or more naturally occurring or non conventional amino acid residues. 
     Deletion encompasses the deletion of one or more amino acid residues. 
     Furthermore, since an inherent problem with native peptides (in L-form) is the degradation by natural proteases, the physiological active protein of the invention may be prepared in order to include D-forms and/or “retro-inverso isomers” of the peptide. Preferably, retro-inverso isomers of short parts, variants or combinations of the physiological active protein of the invention are prepared. 
     Retro-inverso peptides are prepared for peptides of known sequence as described for example in Sela and Zisman, in a review published in FASEB J. 1997 May; 11(6):449-56. 
     By “retro-inverso isomer” is meant an isomer of a linear peptide in which the direction of the sequence is reversed and the chirality of each amino acid residue is inverted; thus, there can be no end-group complementarity. 
     The invention also includes analogs in which one or more peptide bonds have been replaced with an alternative type of covalent bond (a “peptide mimetic”) which is not susceptible to cleavage by peptidases. Where proteolytic degradation of the peptides following injection into the subject is a problem, replacement of a particularly sensitive peptide bond with a noncleavable peptide mimetic will make the resulting peptide more stable and thus more useful as an active substance. Such mimetics, and methods of incorporating them into peptides, are well known in the art. 
     The term “inhibitor” or “antagonist” refers to molecules that inhibit the function of the protein or polypeptide by binding thereto. 
     The term “competitors” refers to “inhibitors” or “antagonists” that directly inhibit the interaction between a protein or polypeptide (i.e. receptor) and its natural ligand resulting in disturbed biochemical or biological function of the receptor. Competitive inhibition is a form of inhibition where binding of the inhibitor prevents binding of the ligand and vice versa. In competitive inhibition, the inhibitor binds to the same active site as the natural ligand, without undergoing a reaction. The ligand molecule cannot enter the active site while the inhibitor is there, and the inhibitor cannot enter the site when the ligand is there. 
     The “biological activity” of a protein refers to the ability to carry out diverse cellular functions and to bind other molecules specifically and tightly. 
     The present invention also includes vaccines and vaccination methods. For example, methods of treating or preventing tumor resistance in a subject suffering from a brain tumor can involve administering to the subject a vaccine composition comprising one or more polypeptides encoded by one or more nucleic acids of one or more genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof or immunologically active fragments of such polypeptides. 
     In the context of the present invention, an immunologically active fragment is a polypeptide that is shorter in length than the full-length naturally-occurring protein yet which induces an immune response analogous to that induced by the full-length protein. For example, an immunologically active fragment should be at least 8 residues in length and capable of stimulating an immune cell, for example, a T cell or a B cell Immune cell stimulation can be measured by detecting cell proliferation, elaboration of cytokines (e.g., IL-2), or production of an antibody. See, for example, Harlow and Lane, Using Antibodies: A Laboratory Manual, 1998, Cold Spring Harbor Laboratory Press; and Coligan, et al., Current Protocols in Immunology, 1991-2006, John Wiley &amp; Sons. 
     Usually the inhibitor of the biological activity of said protein is an antibody or an immunologically fragment thereof that binds to a protein encoded by one or more genes selected from the group comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     Alternatively, function of one or more gene products of the genes over-expressed in cancer can be inhibited by administering a compound that binds to or otherwise inhibits the function of the gene products. For example, the compound is an antibody which binds to the over-expressed gene product or gene products. 
     As used herein, the term “antibody” refers to an immunoglobulin molecule having a specific structure, that interacts (i.e., binds) only with the antigen that was used for synthesizing the antibody (i.e., the gene product of an up-regulated marker) or with an antigen closely related thereto. Furthermore, an antibody can be a fragment of an antibody or a modified antibody, so long as it binds to one or more of the proteins encoded by the marker genes. For instance, the antibody fragment can be Fab, F(ab′) 2 , Fv, or single chain Fv (scFv), in which Fv fragments from H and L chains are ligated by an appropriate linker (Huston J. S. et al., (1988) Proc. Natl. Acad. Sci. U.S.A. 85:5879-83.). More specifically, an antibody fragment can be generated by treating an antibody with an enzyme, including papain or pepsin. Alternatively, a gene encoding the antibody fragment can be constructed, inserted into an expression vector, and expressed in an appropriate host cell (see, for example, Co M. S. et al., (1994) J. Immunol. 152:2968-76; Better M. and Horwitz A. H. (1989) Methods Enzymol. 178:476-96.; Pluckthun A. and Skerra A. (1989) Methods Enzymol. 178:497-515.; Lamoyi E. (1986) Methods Enzymol. 121:652-63.; Rousseaux J. et al, (1986) Methods Enzymol. 121:663-9.; Bird R. E. and Walker B. W. (1991) Trends Biotechnol. 9:132-7.). 
     An antibody can be modified by conjugation with a variety of molecules, for example, polyethylene glycol (PEG). The present invention provides such modified antibodies. The modified antibody can be obtained by chemically modifying an antibody. Such modification methods are conventional in the field. 
     Alternatively, an antibody can comprise a chimeric antibody having a variable region from a nonhuman antibody and a constant region from a human antibody, or a humanized antibody, comprising a complementarity determining region (CDR) from a nonhuman antibody, a frame work region (FR) and a constant region from a human antibody. Such antibodies can be prepared by using known technologies. Humanization can be performed by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody {see, e.g., Verhoeyen et ah, (1988) Science 239:1534-6). Accordingly, such humanized antibodies are chimeric antibodies, wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. 
     Fully human antibodies comprising human variable regions in addition to human framework and constant regions can also be used. Such antibodies can be produced using various techniques known in the art. For example in vitro methods involve use of recombinant libraries of human antibody fragments displayed on bacteriophage (e.g., Hoogenboom &amp; Winter, (1992) J. MoI. Biol. 227:381-8). Similarly, human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. This approach is described, e.g., in U.S. Pat. Nos. 6,150,584; 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016. Such antibodies can be prepared by using known technologies. 
     The present invention also relates to a pharmaceutical composition for the treatment or prevention of a tumor resistance in a subject suffering from a brain tumor, said composition comprising a pharmaceutically effective amount of an antibody or an immunologically fragment thereof that binds to a protein encoded by at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     The present invention also provides a pharmaceutical composition for the treatment or prevention of a tumor resistance in a subject suffering from a brain tumor, said composition comprising a pharmaceutically effective amount of an RNA antisense comprising a nucleotide sequence complementary to a coding sequence of at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     The present invention further provides a pharmaceutical composition for the treatment or prevention of a tumor resistance in a subject suffering from a brain tumor, said composition comprising a pharmaceutically effective amount of an RNA interferent. 
     The present invention further relates to a pharmaceutical composition for the treatment or prevention of a tumor resistance in a subject suffering from the brain tumor, said composition comprising a pharmaceutically effective amount of a compound able to disturb interaction between a protein and a receptor thereof, said protein being encoded by at least one gene selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, biologically active fragment thereof and/or combinations thereof. 
     The present invention also encompasses a pharmaceutical composition for the treatment or prevention of a tumor resistance in a subject suffering from a brain tumor, said composition comprising a pharmaceutically effective amount of a compound obtained with the method of the invention. 
     “A pharmaceutically effective amount” refers to a chemical material or compound which, when administered to a human or animal organism induces a detectable pharmacologic and/or physiologic effect. 
     The respective pharmaceutically effect amount can depend on the specific patient to be treated, on the disease to be treated and on the method of administration. Further, the pharmaceutically effective amount depends on the specific protein used, especially if the protein additionally contains a drug as described or not. The treatment usually comprises a multiple administration of the pharmaceutical composition, usually in intervals of several hours, days or weeks. The pharmaceutically effective amount of a dosage unit of the polypeptide usually is in the range of 0.001 ng to 100 mg per kg of body weight of the patient to be treated. 
     For systemic administration, a therapeutically effective amount or dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. 
     Initial doses can also be estimated from in vivo data, e.g. animal models, using techniques that are well known in the art. One ordinarily skill in the art could readily optimise administration to humans based on animal data and will, of course, depend on the subject being treated, on the subject&#39;s weight, the severity of the disorder, the manner of administration and the judgement of the prescribing physician. 
     “Administering”, as it applies in the present invention, refers to contact of the pharmaceutical compositions to the subject, preferably a human. 
     The pharmaceutical composition may be dissolved or dispersed in a pharmaceutically acceptable carrier well known to those skilled in the art, for parenteral administration by, e.g., intravenous, subcutaneous or intramuscular injection or by intravenous drip infusion. 
     As to a pharmaceutical composition for parenteral administration, any conventional additives may be used such as excipients, adjuvants, binders, disintegrants, dispersing agents, lubricants, diluents, absorption enhancers, buffering agents, surfactants, solubilizing agents, preservatives, emulsifiers, isotonizers, stabilizers, solubilizers for injection, pH adjusting agents, etc. 
     Acceptable carriers, diluents and adjuvants which facilitates processing of the active compounds into preparation which can be used pharmaceutically are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl orbenzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN®, PLURONICS® or polyethylene glycol (PEG). 
     The form of administration of the pharmaceutical composition may be systemic or topical. For example, administration of such a pharmaceutical composition may be various parenteral routes such as subcutaneous, intravenous, intradermal, intramuscular, intraperitoneal, intranasal, transdermal, buccal routes or via an implanted device, and may also be delivered by peristaltic means. 
     The pharmaceutical composition comprising an active ingredient of the present invention may also be incorporated or impregnated into a bioabsorbable matrix, with the matrix being administered in the form of a suspension of matrix, a gel or a solid support. In addition the matrix may be comprised of a biopolymer. 
     Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semi permeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and [gamma]ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. 
     The formulations to be used for in vivo administration must be sterile. This is readily accomplished for example by filtration through sterile filtration membranes. 
     It is understood that the suitable dosage of a peptide of the present invention will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any and the nature of the effect desired. 
     The appropriate dosage form will depend on the disease, the protein, and the mode of administration; possibilities include tablets, capsules, lozenges, dental pastes, suppositories, inhalants, solutions, ointments and parenteral depots. 
     The present invention further relates to a kit for a kit useful for predicting or diagnosing the tumor resistance in a subject treated with concomitant chemo-radiotherapy, said kit comprises a set of primers, probes or antibodies specific for one or more genes selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, G07 genes and G14 genes, biologically active fragment thereof and/or combinations thereof. 
     The cancer-detection reagent of the kit, e.g., a nucleic acid that specifically binds to or identifies one or more nucleic acids associated with tumor resistance to concomitant chemo-radiotherapy, including oligonucleotide sequences which are complementary to a portion of an nucleic acid associated with tumor resistance to concomitant chemo-radiotherapy, or an antibody that binds to one or more proteins encoded by an said nucleic acid. The detection reagents can be packaged together in the form of a kit. For example, the detection reagents can be packaged in separate containers, e.g., a nucleic acid or antibody (either bound to a solid matrix or packaged separately with reagents for binding them to the matrix), a control reagent (positive and/or negative), and/or a detectable label. Instructions (e.g., written, tape, VCR, CD-ROM, etc.) for carrying out the assay can also be included in the kit. The assay format of the kit can be a Northern hybridization or a sandwich ELISA, both of which are known in the art. See, for example, Sambrook and Russell, Molecular Cloning: A Laboratory Manual, 3 rd  Edition, 2001, Cold Spring Harbor Laboratory Press; and Harlow and Lane, Using Antibodies, supra. 
     Also encompassed in the present invention is a method for screening a candidate compound useful in the treatment or prevention of brain tumor, said method comprising the step of: 
     a) contacting said candidate compound with a cell expressing one or more genes selected from gene clusters comprising HOX genes, G13 genes, G18 genes, G25 genes, G07 genes and G14 genes, biologically active fragment thereof and/or combinations thereof,
 
b) selecting the resulting compound that substantially reduces the expression level of one or more genes selected from gene clusters comprising HOX genes, G13 genes, G18 genes, and G25 genes, biologically active fragment thereof and/or combinations thereof, and/or
 
     An agent capable of stimulating the expression of an under-expressed gene or suppressing the expression of an over-expressed gene has clinical benefit. Such agents can be further tested for the ability to prevent cancer in animals or test subjects. As discussed in detail above, by controlling the expression levels of one or more genes of the present invention or the activities of their gene products, one can control the onset and progression of cancer. Thus, candidate agents, which are useful agents in the treatment of cancer, can be identified through screening methods that use such expression levels and activities of as indices of the cancerous or non-cancerous state. 
     The one or more polypeptides encoded by the genes of the present invention to be used for screening can be a recombinant polypeptide or a protein from the nature or a partial peptide thereof. The polypeptide to be contacted with a test compound can be, for example, a purified polypeptide, a soluble protein, a form bound to a carrier or a fusion protein fused with other polypeptides. 
     Many methods are known to those skilled in the art can be used for screening for proteins that bind to the one or more cancer polypeptides encoded by the genes of the present invention. Screening can be conducted by, for example, immunoprecipitation methods, specifically, in the following manner. The one or more marker genes are expressed in host (e.g., animal) cells and so on by inserting the gene to an expression vector for foreign genes, for example, pS V2neo, pcDNA I, pcDNA3.1, pCAGGS and pCD8. The promoter to be used for the expression can be any promoter that can be used commonly and include, for example, the SV40 early promoter (Rigby in Williamson (ed.), (1982) Genetic Engineering, vol. 3. Academic Press, London, 83-141.), the EF-[alpha] promoter (Kim et at., (1990) Gene 91: 217-23.), the CAG promoter (Niwa et al, (1991) Gene 108: 193-9.), the RSV LTR promoter (Cullen, (1987) Methods in Enzymology 152: 684-704.) the SRa promoter (Takebe et al., (1988) MoI Cell Biol 8: 466-72.), the CMV immediate early promoter (Seed and Aruffo, (1987) Proc Natl Acad Sci USA 84: 3365-9.), the SV40 late promoter (Gheysen and Fiers, (1982) J MoI Appl Genet. 1: 385-94.), the Adenovirus late promoter (Kaufman et al., (1989) MoI Cell Biol 9: 946-58.), the HSV TK promoter and so on. The introduction of the gene into host cells to express a foreign gene can be performed according to any methods, for example, the electroporation method (Chu et ah, (1987) Nucleic Acids Res 15: 1311-26.), the calcium phosphate method (Chen and Okayama, (1987) MoI Cell Biol 7: 2745-52.), the DEAE dextran method (Lopata et ah, (1984) Nucleic Acids Res 12: 5707-17.; Sussman and Milman, (1984) MoI Cell Biol 4: 1641-3.), the Lipofectin method (Derijard B5 (1994) Cell 76: 1025-37.; Lamb et ah, (1993) Nature Genetics 5: 22-30.: Rabindran et ah, (1993) Science 259: 230-4.) and so on. 
     The one or more polypeptides encoded by the genes of the present invention can be expressed as a fusion protein comprising a recognition site (epitope) of a monoclonal antibody by introducing the epitope of the monoclonal antibody, whose specificity has been revealed, to the N- or C-terminus of the polypeptide. A commercially available epitope-antibody system can be used (Experimental Medicine 13: 85-90 (1995)). Vectors which can express a fusion protein with, for example, [beta]-galactosidase, maltose binding protein, glutathione S-transferase, green florescence protein (GFP) and so on by the use of its multiple cloning sites are commercially available. 
     A fusion protein prepared by introducing only small epitopes consisting of several to a dozen amino acids so as not to change the property of the polypeptide by the fusion is also reported. 
     Epitopes, including polyhistidine (His-tag), influenza aggregate HA, human c-myc, FLAG, Vesicular stomatitis virus glycoprotein (VSV-GP), T7 gene 10 protein (T7-tag), human simple herpes virus glycoprotein (HSV-tag), E-tag (an epitope on monoclonal phage) and such, and monoclonal antibodies recognizing them can be used as the epitope-antibody system for screening proteins binding to the polypeptide encoded by marker genes (Experimental Medicine 13: 85-90 (1995)). 
     EXAMPLES 
     Example 1 
     Material and Methods 
     Gene expression profiles of 80 glioblastoma were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy. 
     Tumor Samples and Patient Characteristics 
     Gene expression profiles were established from 80 frozen GBM samples obtained from 76 patients, comprising 70 tumors from initial surgery, and 10 samples resected at recurrence, and from four non-neoplastic brain tissue samples. All patients were treated within a phase II, or a randomized phase III trial {Stupp, 2005 #2126} and provided written informed consent for molecular studies of their tumor. The protocol was approved by the ethics committee at each center. Sixty-eight patients with complete molecular and clinical information were included in survival analysis, with a median age of 51 years (range: 26-70 yrs) at enrollment. Thereof, 42 received TMZ/RT→TMZ, while 26 were randomized to RT only. Second-line therapy frequently involved alkylating agents including TMZ. Patient characteristics are summarized in Table 3. The validation set comprised 76 independent patients of the EORTC/NCIC-study (Stupp et al., 2005), 39 randomized to TMZ/RT→TMZ, and 37 to RT (median age 54 yrs, range 25-69 yrs), whose GBM were available on a tissue microarray. There was no difference in survival as compared to the general trial population, neither in the test population, nor the validation set (P&gt;0.2). 
     Gene Expression Profiling 
     Total RNA was extracted from frozen tumor sections (10-15 mg) (Qiagen, RNeasy-Lipid Tissue Kit). The first section served as reference for diagnosis and tumor content (&gt;70%). Probes were prepared with the ENZO BioArray-HighYield Kit for double amplification and were hybridized to Affymetrix HG-133Plus2.0 GeneChips. The microarray data is deposited in the Gene Expression Omnibus (GEO) database at http://www.ncbi.nml.nih.gov/geo/; (accession-number GSE7696). Quantitative reverse transcription polymerase-chain reaction (qRT-PCR) was performed on the ABI Prism7900 with SYBR Green (Applied Biosystem). Primers are listed in Table 4. Results were normalized to the expression of the EIF2C3, DNAJA4 and B2M genes that exhibit little variation in this dataset. 
     Data Analysis and Statistical Methods 
     Analyses were carried out in R, a free software environment available at http://www.r-project.org/, SAS (V9.1.3), or Coupled Two Way Clustering (CTWC)(Getz et al., 2000) available at: http://ctwc.weizmann.ac.il. The expression intensities for all probe-sets from Affymetrix CEL-files were estimated using robust multi-array average (RMA) with probe-level quantile normalization followed by median polish summarization as implemented in the BioConductor software (http://www.bioconductor.org/). 
     The expression matrix of 84 samples and 3,860 most variable probe-sets (standard deviation&gt;0.75) was inputed into CTWC using default parameters, and two levels of clustering. CTWC analysis can be viewed at: http://bcf.isb-sib.ch/projects/cancer/glio/. Probe-sets comprised in stable gene clusters emerging from CTWC served as input for supervised analyses. 
     The Benjamini-Hochberg procedure was applied for multiple testing correction (FDR). 
     
       
         
           
               
             
               
                   
               
               
                 Cox Survival Models Used for Individual Data Sets 
               
               
                 Data Sets 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Hegi42 (TMZ/RT) 
                 y~β 1 meanCluster + β 2  MGMT + β 3   
               
               
                   
                 age 
               
               
                 Hegi42 (TMZ/RT) 
                 y~β 1 EGFRvIII + β 2  MGMT + β 3  age + β 4  EGFRwt 
               
               
                 Hegi42 (TMZ/RT) 
                 y~β 1 meanG98 + β 2  EGFR + β 3  MGMT + β 4  age 
               
               
                 Hegi68 (all, G98) 
                 y~β 1 meanG98 + β 2  MGMT + β 3  age + β 4  TMZ + 
               
               
                   
                 β 5  meanG98:TMZ + β 6  MGMT:TMZ 
               
               
                 Hegi68 (all, EGFR) 
                 y~β 1  EGFR + β 2  MGMT + β 3 age + β 4  TMZ + 
               
               
                   
                 β 5  EGFR:TMZ + β 6  MGMT:TMZ 
               
               
                 Nelson 
                 y~β 1 meanCluster + β 2  grade + β 3  age 
               
               
                 Aldape 
                 y~β 1 meanCluster + β 2  grade + β 3  age 
               
               
                 combined 
                 y~β 1 meanCluster + β 2  grade + β 3  age + 
               
               
                   
                 strata (dataSet) 
               
               
                   
               
               
                 MGMT, methylation status 
               
               
                 MGMT:TMZ, interaction factor with TMZ/RT→TMZ therapy 
               
            
           
         
       
     
     Partial Least Square (PLS) 
     Partial Least Square (PLS) regression is a technique that combines features from principal component analysis and from multiple linear regression  s . It is particularly useful to predict an outcome from a large set of highly correlated predictors. In the present invention, the PLS procedure in SAS was used to define combinations of the genes expressions (i.e. factors) which attempt to explain the genes expressions variability and the survival outcome at the same time. For each patient, the martingale residuals obtained from a Cox regression with a constant as the only predictor were used as outcome variable to be explained  s . This approach was derived from the works of Therneau et al.  s  and Leblanc et al.  s  with the CART algorithm and applied to PLS regression. This allowed to account for the effect of censoring on survival estimates. 
     The optimal number of PLS factors is generally obtained by cross validation, but in this small sample (n=42 or 68) this method was not conclusive (i.e. no optimal number of factors could be obtained). Therefore, we empirically chose to fit a PLS model with two factors to minimize overfitting and get interpretable results. The two factors explained 66% of the survival outcome variations. The contribution of each gene was assessed by their coefficients in the linear regression and their X-weights plotted in a factorial plane. Arbitrarily, clusters were given X-weights by averaging the X-weights of their constituent genes. 
     Tissue Micro Array (TMA) and Immunohistochemistry 
     The TMA was constructed with glioblastoma from the EORTC/NCIC-trial (Stupp et al., 2005). HOXA10 (Santa Cruz, sc-17159; dilution 1:200) expression was determined by immunohistochemistry (citrate buffer ph 6.0, 15 min pressure cooker) and scored without knowledge of clinical information on a scale of 0 to 6 (0, no expression; 1, weak nuclear expression in &lt;20% cells; 2, strong in &lt;20% cells; 3, weak in 20 to 50% cells; 4, strong in 20 to 50% cells; 5, weak in &gt;50% cells; 6, strong in &gt;50% cells). Dichotomization for survival analysis was no-low (0,1) versus intermediate-high expression (2-6). Frozen sections of neurospheres were fixed with acetone and stained for HOXA10 and CD133 (Santa Cruz, sc-17159, dilution 1:100; Miltenyi AC133-2, 293C3, dilution 1:50). 
     Glioblastoma Derived Neurospheres 
     Fresh glioblastoma tissue was dissociated in presence of papain and DNase I basically as described (Clement et al., 2007). Cells were cultured under stem cell conditions to form spheres using Dulbecco&#39;s modified Eagle medium/F12 medium containing B27 supplement and 20 ng/ml of both EGF and FGF2. Neurospheres from 6 glioblastoma propagated between 4 weeks and 14 months were used for immunostaining. 
     Description of External Data Sets 
     Two external gene expression data sets (GeneChip U133A &amp; B, Affymetrix) of malignant glioma were used for validation of survival factors, referred to as “Nelson-”  s (Freije et al., 2004) and “Aldape-” data sets  s (Phillips et al., 2006), respectively. Only cases with diagnosis of glioblastoma, astrocytoma grade III, and mixed-oligoastrocytoma grade III were included. The Nelson data set utilized here comprised 17 grade III and 54 grade IV glioma. The median age was 43 years at diagnosis for all 71 patients, or 51 years for GBM patients, respectively. The Aldape data set consisted of 75 patients, 27 grade III, 48 grade IV with a median age at diagnosis of 47 years for all cases, or 49 years for GBM patients, respectively. This data set was enriched for long term survivors according to the authors. Adjustments in the Cox models for these two external glioma validation sets comprised age as a dichotomous variable (&gt;50 years) and tumor grade. 
     In addition, we used a mouse expression data set published by Krivtsov et al.  s (Krivtsov et al., 2006) and a human leukemia data set by Ross et al.  s (Ross et al., 2004) Table 9. For both human malignant glioma validation sets, only the chips that passed quality criteria based on the BioConductor library affyPLM  s  were included. The external data sets were each separately normalized using RMA, when CEL-files were available (Aldape, Nelson and Ross). For the Krivtsov mouse expression data set  s (Krivtsov et al., 2006), the Affymetrix Microarray Suite version 5.0 processed data, as submitted in the Gene Expression Omnibus (GEO) database, were used. For the human-murine comparison, we mapped the human gene sets to homolog murine gene sets using the annotation provided by Affymetrix on their webpage http//www.affymetrix.com (version of Nov. 14, 2006). For GSEA analysis the data sets were filtered to retain only the most variant probe sets (standard deviation greater than 0.5). 
     Supervised Analysis 
     For each covariate, the hazards ratio, its 95% confidence interval and the associated Wald p-value were examined The Benjamini Hochberg procedure  s  was applied as multiple testing correction method to convert p-values into estimated false discovery rates (FDR). The hazards ratio for a gene (or the mean of a cluster) were standardized by referring them to a variation corresponding to an interquartile range, in order to obtain an interpretable value, for microarray as well as for real-time PCR data. Therefore, the interpretation of an estimated hazard ratio of 1.5 is that the hazard rate increases by 50 percent for an increase of one interquartile range of the log-scale gene expression, independently of the expression level at which it is calculated. 
     Example 2 
     Results 
     An expression signature dominated by HOX-genes which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemo-radiotherapy (n=42; hazard ratio 2.69, 95% CI 1.38-5.26, P=0.004). This association could be validated in an independent data-set. Provocatively, the HOX-gene cluster was reminiscent of a “self-renewal” signature (P=0.008; Gene Set Enrichment Analysis). The HOX-gene signature and EGFR-gene expression were independent prognostic factors in multivariate analysis, adjusted for the MGMT-methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor host interaction including tumor vascularization and cell adhesion, and innate immune response. 
     Gene Expression Signatures Associated with Tumor Resistance There was no obvious association of patient characteristics or survival with genetic subtypes evident from the sample dendrogram S1(G1), clustering all samples (S1) and all genes (G1) passing a variation filter ( FIG. 1A ). The methylation status of the MGMT gene promoter appears to be randomly distributed. All stable gene clusters emerging from this analysis are listed in Table 1, named by the predominant biological function suggested by the genes they comprise, while their inter-relationship is visualized in  FIG. 1B . 
     Similar gene clusters are obtained when using only the subset of glioblastoma clustered in S4 [G1(54)] (Table 5). 
     Cluster S4 comprises most glioblastoma (69/80), but not the non-tumoral tissues that form their own stable cluster S3 ( FIG. 1A ). Similar gene clusters are present in other glioblastoma data-sets as visualized in  FIG. 1C  for data-sets published by the group of Nelson and Aldape, respectively (Freije et al., 2004; Phillips et al., 2006). All eighteen non-overlapping, stable gene clusters [G1(S1)] were interrogated for association with survival using Cox proportional hazards, adjusted for age (&gt;50 years) and MGMT methylation status (Hegi et al., 2005). Seven gene clusters were most influential for explaining survival in patients randomized to TMZ/RT→TMZ (Table 1; gene lists, Tables A8-A13). A respective PLS-model yielded comparable results ( FIG. 5 ). However, the MGMT methylation status was yet the most influential predictor of survival (Table 2,  FIG. 5 ). In this invention, the Applicants identified and focused on the two most significant clusters characterized by HOX (G28/G98 clusters) and EGFR gene expression (G25 clusters) and other relevant gene clusters presented in the present invention. 
     “Self-Renewal Signature” Associated with Resistance to Chemo-Radiotherapy in Glioblastoma 
     Increased expression of cluster G28, dominated by HOX-genes and comprising the cell-cycle checkpoint gene GADD45G (Vairapandi et al., 2002), was found to be associated with worse outcome (P=0.004; HR 2.69, 95% CI 1.38-5.26; Table 1). The interaction term between this HOX-gene cluster and chemo-radiotherapy was significant (P=0.001) in the Cox model, when evaluating all 68 patients from the two treatment arms, implying that high expression of HOX-genes may be predictive for resistance to TMZ/RT→TMZ therapy. 
     The HOX gene clusters G28 and G98 emerging from clustering all genes (G1) either with all samples (S1) or only with glioblastoma clustered in S4, are almost identical (Pearson correlation0.98; 19/21 probe-sets, Table 7). 
     Intriguingly, G98 in addition comprises PROM1 (prominin 1) encoding the putative glioma stem cell marker CD133 ( FIG. 2A ), suggesting that in a subpopulation of glioblastoma concerted upregulation of HOX-genes might be associated with a tumor stem-like cell phenotype. In accordance, we find high HOXA10 protein expression in glioblastoma derived neurospheres, cultured under stem cell conditions, as displayed in  FIG. 2B  together with CD133 expression. To include information on PROM1 the Applicant&#39;s show results on G98 for all following analyses.  FIG. 2C  visualizes the association of short survival with enhanced expression of G98. 
     Validation in Independent Datasets 
     The association of the HOX-signature with resistance to treatment was subsequently validated in a sample set of the trial not available for initial discovery, arrayed on a TMA. HOXA10 was evaluated by immunohistochemistry ( FIG. 3A ) as a representative of the correlated set of HOX-genes. Strong nuclear expression was often observed in patches of tumor cells, situated in the vicinity of blood vessels. High HOXA10 expression was associated with worse outcome in patients randomized to TMZ/RT→TMZ therapy (n=39, HR 2.57, 95% CI 1.21-5.47, p=0.014) ( FIG. 3B ). The patients randomized to RT only did not show such a relationship, suggesting that high HOXA10 expression may be predictive for resistance to a synergistic effect of concomitant chemo-radiotherapy, in concordance with the significant interaction term between treatment and expression of G28 or G98 (Table 6). 
     Similar HOX-gene clusters can be identified in the Nelson and Aldape glioblastoma datasets (Freije et al., 2004; Phillips et al., 2006). Correlating G98 gene expression with outcome in these datasets totaling 102 glioblastoma revealed a trend for worse outcome (P=0.09, HR 1.29, 95% CI 0.97-1.72) ( FIG. 6 ). Of note, in contrast to our data, these patients were treated before the TMZ/RT→TMZ regimen was established. In accordance with better survival, anaplastic glioma (WHO grade III) profiled in these publications revealed significantly lower expression of G98 genes as compared to glioblastoma (WHO grade IV) (P&lt;0.001 Aldape data-set (Freije et al., 2004); P=0.002, Nelson data-set (Phillips et al., 2006), Wilcoxon rank sum test with continuity correction,  FIG. 7 ). However, within grade III glioma of the two data-sets increased expression of G98 genes was associated with worse outcome (n=44, p=0.007, HR 3.35, 95% CI 1.39-8.08,  FIG. 6 ). 
     HOX-Signature Reminiscent of “Self-Renewal” 
     The Applicant&#39;s G98-derived signature was significantly enriched in genes discriminating “self-renewal” versus “non-self-renewal” in this expression dataset according to Gene Set Enrichment Analysis (GSEA) (Subramanian et al., 2005) (P=0.008) ( FIG. 8 ) and the Wilcoxon two-sample test (G98, P&lt;0.001). The relevance of our signature was further demonstrated in a human dataset (Ross et al., 2004) in which G98, similar to the original murine “self-renewal signature” (Krivtsov et al., 2006), was able to significantly differentiate MLL rearranged AML from AML (GSEA, P&lt;0.001; Wilcoxon two-sample test, P=0.01) Table 9. 
     Interestingly, a significant, though low correlation between the mean DNA copy number of the two BAC (bacterial artificial chromosome) clones (GS1-213H12 and CTB-23D20) bordering the HOXA gene locus on chromosome 7 and the mean expression of the HOXA genes was observed in a set of 60 glioblastoma (Pearson correlation coefficient r=0.27, P=0.03) (manuscript in preparation). These flanking BACs were more amplified than their neighbors ( FIG. 9 ). Hence, the here HOX-dominated “self-renewal signature” for glioblastoma may in part be acquired by increased gene dosage. 
     High EGFR Expression is Associated with Tumor Resistance. 
     Two gene clusters representing amplification-mediated overexpression of proto-oncogenes were associated with tumor resistance: G13 (P=0.02, HR 1.1, 95% CI 1.0-1.2) characterized by coordinated upregulation of contiguous genes on chromosome 12q13-15, comprising the proto-oncogenes CDK4 and MDM2, and G25, dominated by EGFR probesets (P=0.002, HR, 2.8, 95% CI 1.4-5.4) (Table 1,  FIG. 4 ). The array-derived EGFR-measurement (probeset 201983_s_at) was confirmed by qRT-PCR (Pearson correlation 0.89). Expression of the constitutively activated EGFRvIII mutant (18/70; 26%), as measured by qRT-PCR, did not further influence outcome prediction (P=0.94). 
     Cluster G18, associated with tumor resistance (P=0.03; HR 1.94, 95% CI 1.07-3.51), displayed some correlation with EGFR expression (r=0.57) ( FIG. 1B ) in particular with Aquaporin 4 (AQP4). AQP4 has been associated with brain tumor related edema (Manley et al., 2000). Aquaporins require activation of mitogen-activated protein kinase (MAPK) signalling that may be mediated by EGFR activation (Herrlich et al., 2004). Another family member, AQP1, has been linked with tumor angiogenesis and cell migration (Saadoun et al., 2005) and was associated with worse outcome in the present invention (P=0.003; HR: 2.44, 95% CI: 1.36-4.04) and in the two external datasets (combined P=0.009; HR=1.51; 95% CI 1.11-2.06). 
     Blood Vessels Markers Associated with Better Outcome. 
     G7 is characterized by genes associated with endothelial cells, basement membranes, signaling pathways of vascular development and angiogenesis, and tumor-derived endothelial markers (Madden et al., 2004; St Croix et al., 2000) (Table 10). 
     Hence, G7 may differentiate tumors according to their angiogenic pattern that may be indicative for drug perfusion and therefore show association with benefit from treatment (Table 1). G7 is in the center of a “super cluster” ( FIG. 1B ) constituted of several stable gene clusters with biologically related features, such as hypoxia regulated genes G9, and the myeloid progenitor/adhesion cluster G14, which is also correlated with better outcome (Table 1). Beside genes related to cell adhesion, mesenchymal stem cells (PRR16), and homeobox genes (MEOX1, MKX), G14 includes aldehyde dehydrogenase (Chute et al., 2006) and bone morphogenetic protein 5 (BMP5) (Piccirillo et al., 2006) both associated with differentiation of stem-cells. The cluster comprises positive (MEOX1) and negative regulators (SOSTDC1) of BMPs, which recently have been shown to inhibit tumorigenic potential of human brain tumor stem cells by promoting their differentiation (Piccirillo et al., 2006). This cluster may reflect the perivascular microenvironment proposed recently to serve as niche for brain tumor stem cells (Calabrese et al., 2007). 
     Innate Immune Response Associated with Better Survival. 
     Alongside markers of innate immunity and macrophages (CD11b), G24 comprises numerous cell surface receptors known as markers for M2 polarized macrophages (Mantovani et al., 2002), such as CD163 (Table 14). M2-polarization mediates tolerance and down-regulates inflammation, alleviating immune surveillance (Mantovani et al., 2002). A wide range of CD163 positive cells can be observed in glioblastoma ( FIG. 10 ). The cluster also contains probes encoding MHC class II surface molecules, but lacks expression of co-stimulatory molecules critical for T-cell activation. This immune signature may be relevant for strategies of tumor vaccination. 
     HOX-Signature and EGFR Expression are Independent Prognostic Factors. 
     Multivariate analysis suggests that the HOX-signature and EGFR expression, respectively, are independent prognostic factors for poor outcome in TMZ/RT→TMZ treated glioblastoma patients, explaining 67% of the survival outcome variations together with the MGMT-status and age (Table 2). 
     Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein. 
     Various references are cited throughout this Specification, each of which is incorporated herein by reference in its entirety. 
     The foregoing description will be more fully understood with reference to the following Examples. Such Examples, are, however, exemplary of methods of practising the present invention and are not intended to limit the scope of the invention. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Cox Analysis Using Stable Gene Clusters Identified in G1(S1) in the Cohort of 
               
               
                 Treated Patients (n = 42) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 # 
                   
                   
                   
                   
               
               
                   
                   
                   
                 Probes 
               
               
                 From G1 (S1) 
                   
                   
                 in 
                   a P- 
               
               
                 Main Clusters 
                 Subclusters 
                 Description 
                 Cluster 
                 Value 
                   b FDR 
                   c HR 
                 95% CI 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 G2 
                   
                 Migration-related 
                 19 
                 0.21 
                 0.32 
                 0.73 
                 0.45 
                 1.19 
               
               
                 G7 
                   
                 Tumor Blood Vessel Markers 
                 77 
                 0.04 
                 0.11 
                 0.73 
                 0.54 
                 0.99 
               
               
                 G9 
                   
                 Hypoxia-induced 
                 32 
                 0.70 
                 0.78 
                 0.89 
                 0.49 
                 1.61 
               
               
                 G11 
                   
                 SOX Genes 
                 15 
                 0.25 
                 0.34 
                 1.46 
                 0.77 
                 2.77 
               
               
                 G12 
                   
                 Interferon-induced Genes 
                 80 
                 0.78 
                 0.83 
                 1.06 
                 0.72 
                 1.55 
               
               
                 G13 
                   
                 Chromosome 12 
                 39 
                 0.02 
                 0.09 
                 1.13 
                 1.02 
                 1.24 
               
               
                 G14 
                   
                 Myeloid Lineage/Adhesion 
                 26 
                 0.03 
                 0.09 
                 0.61 
                 0.39 
                 0.95 
               
               
                 G16 
                   
                 Glial Lineage 
                 49 
                 0.07 
                 0.16 
                 1.64 
                 0.96 
                 2.81 
               
               
                 G18 
                   
                 Brain Physiology 
                 25 
                 0.03 
                 0.09 
                 1.94 
                 1.07 
                 3.51 
               
               
                 G20 
                   
                 ?? 
                 24 
                 0.20 
                 0.32 
                 1.36 
                 0.85 
                 2.19 
               
               
                 G21 
                 &gt;G17 &gt; G10 &gt; G3 
                 Neural Genes 
                 213 
                 0.99 
                 0.99 
                 1.00 
                 0.69 
                 1.46 
               
               
                 G22 
                   
                 Imprinted Genes 
                 34 
                 0.20 
                 0.32 
                 0.65 
                 0.34 
                 1.25 
               
               
                 G23 
                 &gt;G19 &gt; G4 
                 Oligodendrocyte Markers 
                 110 
                 0.66 
                 0.78 
                 1.07 
                 0.78 
                 1.47 
               
               
                 G24 
                 &gt;G15 &gt; G8 
                 Innate Immune Response 
                 134 
                 0.03 
                 0.09 
                 0.65 
                 0.44 
                 0.96 
               
               
                 G25 
                   
                 EGFR 
                 18 
                 0.002 
                 0.03 
                 2.78 
                 1.44 
                 5.36 
               
               
                 G27 
                 &gt;G5 
                 Spermatogenesis 
                 79 
                 0.10 
                 0.20 
                 1.38 
                 0.94 
                 2.03 
               
               
                 G28 
                   
                 HOX Genes 
                 20 
                 0.004 
                 0.03 
                 2.69 
                 1.38 
                 5.26 
               
               
                 G29 
                 &gt;G26 &gt; G6 
                 Proliferation 
                 101 
                 0.43 
                 0.55 
                 1.27 
                 0.70 
                 2.32 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Overall Cox Proportional-Hazards Models for the Cohort of 42 Patients 
               
               
                 Treated with TMZ/RT→TMZ 
               
            
           
           
               
               
               
            
               
                   
                 Univariate Model 
                 Multivariate Model 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Hazard Ratio 
                   
                   
                 Hazard Ratio 
                   
                   
               
               
                 Variables 
                 (95% CI) 
                 P-Value 
                 R 2   
                 (95% CI) 
                 P-Value 
                 R 2   
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 HOX cluster (G98), mean 
                 1.89 (1.03-3.46) 
                 0.04 
                 0.10 
                 3.32 (1.61-6.82) 
                 0.001 
                   a 0.67 
               
               
                 expression 
               
               
                 EGFR expression 
                 1.87 (1.09-3.22) 
                 0.02 
                 0.12 
                 3.13 (1.62-6.04) 
                 &lt;0.001 
               
               
                 MGMT-methylation 
                 0.15 (0.06-0.37) 
                 &lt;0.001 
                 0.38 
                 0.06 (0.0-0.20) 
                 &lt;0.001 
               
               
                 Age &gt;50 years 
                 1.89 (0.93-3.83) 
                 0.08 
                 0.07 
                 2.61 (1.22-5.57) 
                 0.01 
               
               
                   
               
               
                 HR, Hazard Ratio; 
               
               
                 CI, confidence interval 
               
               
                   a R 2  for the overall multivariate Cox Proportional-Hazards Model. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Summary of patient information 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 Patient 
                   
                   
                 MGMT 
                 OS 
                   
                   
                   
               
               
                 Tissue a   
                 Id 
                 Rec Id 
                 Gender 
                 status 
                 months 
                 Age 
                 Treatment b   
                 Censor 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 GBM 
                 12 
                   
                 M 
                 M 
                 17 
                 38 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 15 
                   
                 F 
                 U 
                 6 
                 45 
                 RT 
                 uncensored 
               
               
                 GBM 
                 30 
                   
                 M 
                 M 
                 7 
                 61 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 55 
                   
                 M 
                 M 
                 10 
                 50 
                 RT 
                 uncensored 
               
               
                 GBM 
                 57 
                 57R 
                 M 
                 M 
                 36 
                 53 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 GBM 
                 63 
                   
                 M 
                 M 
                 16 
                 49 
                 RT 
                 uncensored 
               
               
                 RecGBM 
                   
                 65R 
                 F 
                 M 
                 13 
                 46 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 70 
                   
                 M 
                 ? 
                 34 
                 53 
                 RT 
                 censored 
               
               
                 GBM 
                 80 
                   
                 F 
                 M 
                 30 
                 47 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 83 
                   
                 M 
                 U 
                 16 
                 49 
                 RT 
                 uncensored 
               
               
                 GBM 
                 84 
                   
                 M 
                 M 
                 1 
                 54 
                 RT 
                 uncensored 
               
               
                 GBM 
                 90 
                   
                 F 
                 M 
                 30 
                 61 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 GBM 
                 93 
                   
                 M 
                 U 
                 10 
                 70 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 94 
                   
                 M 
                 U 
                 9 
                 59 
                 RT 
                 uncensored 
               
               
                 GBM 
                 97 
                   
                 F 
                 U 
                 4 
                 62 
                 RT 
                 uncensored 
               
               
                 RecGBM 
                   
                 100R 
                 M 
                 U 
                 24 
                 64 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 104 
                   
                 M 
                 M 
                 20 
                 56 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 106 
                   
                 M 
                 U 
                 10 
                 27 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 129 
                   
                 M 
                 U 
                 4 
                 49 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 147 
                   
                 M 
                 M 
                 15 
                 49 
                 RT 
                 uncensored 
               
               
                 norm. brain 
                 148 
                   
                   
                   
                   
                   
                   
                 NA 
               
               
                 RecGBM 
                   
                 155R 
                 M 
                 M 
                 21 
                 52 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 157 
                   
                 M 
                 U 
                 8 
                 49 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 159 
                   
                 F 
                 U 
                 14 
                 61 
                 RT 
                 uncensored 
               
               
                 GBM 
                 161 
                   
                 M 
                 U 
                 12 
                 53 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 190 
                   
                 M 
                 M 
                 17 
                 61 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 211 
                   
                 M 
                 M 
                 9 
                 44 
                 RT 
                 uncensored 
               
               
                 RecGBM 
                   
                 212R 
                 F 
                 U 
                 16 
                 59 
                 RT 
                 uncensored 
               
               
                 GBM 
                 218 
                   
                 F 
                 M 
                 16 
                 48 
                 RT 
                 uncensored 
               
               
                 GBM 
                 222 
                   
                 F 
                 U 
                 12 
                 62 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 236 
                   
                 M 
                 U 
                 11 
                 57 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 242 
                   
                 M 
                 U 
                 14 
                 54 
                 RT 
                 uncensored 
               
               
                 GBM 
                 246 
                   
                 M 
                 M 
                 23 
                 54 
                 RT 
                 uncensored 
               
               
                 GBM 
                 254 
                   
                 M 
                 U 
                 7 
                 64 
                 RT 
                 uncensored 
               
               
                 GBM 
                 269 
                   
                 M 
                 U 
                 7 
                 61 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 274 
                   
                 F 
                 U 
                 9 
                 49 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 283 
                   
                 M 
                 M 
                 7 
                 57 
                 RT 
                 uncensored 
               
               
                 GBM 
                 284 
                   
                 M 
                 M 
                 27 
                 52 
                 RT 
                 uncensored 
               
               
                 GBM 
                 288 
                   
                 M 
                 M 
                 27 
                 45 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 GBM 
                 300 
                   
                 M 
                 ? 
                 9 
                 47 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 323 
                   
                 M 
                 M 
                 16 
                 53 
                 RT 
                 uncensored 
               
               
                 GBM 
                 328 
                   
                 M 
                 U 
                 11 
                 63 
                 RT 
                 uncensored 
               
               
                 GBM 
                 344 
                   
                 M 
                 U 
                 16 
                 57 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 345 
                   
                 M 
                 M 
                 6 
                 59 
                 RT 
                 uncensored 
               
               
                 GBM 
                 349 
                   
                 F 
                 M 
                 14 
                 52 
                 RT 
                 uncensored 
               
               
                 GBM 
                 356 
                   
                 M 
                 U 
                 7 
                 32 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 360 
                   
                 F 
                 M 
                 23 
                 56 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 GBM 
                 390 
                   
                 M 
                 U 
                 16 
                 42 
                 RT 
                 uncensored 
               
               
                 GBM 
                 396 
                   
                 M 
                 M 
                 16 
                 50 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 GBM 
                 428 
                   
                 M 
                 M 
                 9 
                 57 
                 RT 
                 uncensored 
               
               
                 GBM 
                 444 
                   
                 M 
                 M 
                 6 
                 63 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 458 
                   
                 F 
                 U 
                 14 
                 50 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 461 
                   
                 M 
                 U 
                 15 
                 64 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 506 
                   
                 M 
                 U 
                 6 
                 57 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 527 
                   
                 F 
                 M 
                 24 
                 53 
                 RT 
                 censored 
               
               
                 GBM 
                 528 
                   
                 M 
                 U 
                 24 
                 33 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 GBM 
                 534 
                   
                 F 
                 M 
                 23 
                 42 
                 RT 
                 censored 
               
               
                 GBM 
                 547 
                   
                 M 
                 U 
                 17 
                 43 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 558 
                   
                 F 
                 U 
                 6 
                 56 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 563 
                   
                 M 
                 U 
                 9 
                 53 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 566 
                   
                 M 
                 U 
                 16 
                 44 
                 RT 
                 uncensored 
               
               
                 GBM 
                 574 
                   
                 F 
                 U 
                 5 
                 44 
                 RT 
                 uncensored 
               
               
                 norm. brain 
                 1076 
                   
                   
                   
                   
                   
                   
                 NA 
               
               
                 GBM 
                 1284 
                   
                 F 
                 M 
                 47 
                 48 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 1297 
                   
                 M 
                 M 
                 60 
                 36 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 1308 
                   
                 F 
                 M 
                 17 
                 45 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 1317 
                   
                 M 
                 U 
                 17 
                 26 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 1357 
                   
                 M 
                 M 
                 28 
                 36 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 1360 
                   
                 M 
                 M 
                 9 
                 65 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 1399 
                   
                 M 
                 M 
                 79 
                 39 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 GBM 
                 1430 
                 1497R 
                 M 
                 M 
                 15 
                 37 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 1437 
                   
                 M 
                 U 
                 16 
                 48 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 GBM 
                 1453 
                   
                 F 
                 U 
                 9 
                 53 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 norm. brain 
                 1553 
                   
                   
                   
                   
                   
                   
                 NA 
               
               
                 GBM 
                 1621 
                 1622R 
                 M 
                 M 
                 25 
                 62 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                 norm. brain 
                 1780 
                   
                   
                   
                   
                   
                   
                 NA 
               
               
                 RecGBM 
                 1795R 
                 1869RR 
                 M 
                 M 
                 72 
                 43 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 RecGBM 
                   
                 1854R 
                 M 
                 M 
                 63 
                 52 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 GBM 
                 ge197 
                   
                 M 
                 M 
                 53 
                 46 
                 TMZ/RT→TMZ 
                 censored 
               
               
                 GBM 
                 ge205 
                   
                 F 
                 M 
                 23 
                 56 
                 TMZ/RT→TMZ 
                 uncensored 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Primer Sequences Used in qRT-PCR 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
               
               
                   
                   
                   
                 ID 
               
               
                 Target 
                   
                 Primer Sequences 
                 N o   
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 EIF2C3 
                 Forward 
                 5′-CTACATTGTAGTTCAGAAGAGACATC 
                 1 
               
               
                   
                 primer 
                 ACA-3′ 
                   
               
               
                   
                 Reverse 
                 5′-TGCCACTTCTTCCAACCCTTT-3′ 
                 2 
               
               
                   
                 primer 
                   
                   
               
               
                   
               
               
                 DNAJA4 
                 Forward 
                 5′-GGATGAGGGCGAGAAGTTTAAA-3′ 
                 3 
               
               
                   
                 primer 
                   
                   
               
               
                   
                 Reverse 
                 5′-GGTCATAAACATCCCTTTTCTTTGG-3′ 
                 4 
               
               
                   
                 primer 
                   
                   
               
               
                   
               
               
                 B2M 
                 Forward 
                 5′-TGCTCGCGCTACTCTCTCTTT-3′ 
                 5 
               
               
                   
                 primer 
                   
                   
               
               
                   
                 Reverse 
                 5′-TCTGCTGGATGACGTGAGTAAAC-3′ 
                 6 
               
               
                   
                 primer 
                   
                   
               
               
                   
               
               
                 EGFRwt 
                 Forward 
                 5′-GTGGTCCTTGGGAATTTGGA-3′ 
                 7 
               
               
                   
                 primer 
                   
                   
               
               
                   
                 Reverse 
                 5′-CACCTCCTGGATGGTCTTTAAGA-3′ 
                 8 
               
               
                   
                 primer 
                   
                   
               
               
                   
               
               
                 EGFRvIII 
                 Forward 
                 5′-CGCTGCTGGCTGCGCTCTG-3′ 
                 9 
               
               
                   
                 primer 
                   
                   
               
               
                   
                 Reverse 
                 5′-AGATGGAGGAAGACGGCGT-3′ 
                 10 
               
               
                   
                 primer 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Cox analysis using G1 (S4) clusters in the TMZ/RT treated patient cohort (n = 42) 
               
            
           
           
               
               
               
            
               
                   
                 Stable Clusters in G1 (S4) 
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   a S1vs S4 
                 Main 
                   
                   
                   
                   
                   
                   
                   
               
               
                 clusters 
                 Clusters 
                 Subclusters 
                 Description 
                 # probes 
                   b p-value 
                   c FDR 
                   d HR 
                 95% CI 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 pG02 
                 G71 
                   
                 Astrocyte Markers (?) 
                 17 
                 0.03 
                 0.11 
                 0.58 
                 0.36 
                 0.96 
               
               
                 pG02/pG07 
                 G72 
                   
                 Migration-related 
                 17 
                 0.29 
                 0.49 
                 0.76 
                 0.46 
                 1.26 
               
               
                 G23 
                 G74 
                   
                 Oligodendrocyte Markers 
                 79 
                 0.67 
                 0.87 
                 1.07 
                 0.79 
                 1.44 
               
               
                 G24/pG07 
                 G80 
                   
                 Innate Immune Response 
                 152 
                 0.03 
                 0.11 
                 0.62 
                 0.41 
                 0.94 
               
               
                 G29 
                 G82 
                 &gt;G77 
                 Proliferation 
                 98 
                 0.47 
                 0.72 
                 1.26 
                 0.67 
                 2.36 
               
               
                 G13 
                 G83 
                   
                 Chromosome 12 
                 37 
                 0.02 
                 0.11 
                 1.08 
                 1.01 
                 1.15 
               
               
                 G09 
                 G84 
                   
                 Hypoxia-induced Genes 
                 54 
                 0.51 
                 0.72 
                 0.83 
                 0.47 
                 1.45 
               
               
                   
                 G88 
                   
                 ? TGF-beta, myc, SOD2 
                 20 
                 0.08 
                 0.22 
                 0.68 
                 0.44 
                 1.05 
               
               
                 G07 pG14 
                 G90 
                 &gt;G79 &gt; G73; G85 
                 Tumour Blood Vessel Markers/Adhesion 
                 131 
                 0.01 
                 0.10 
                 0.60 
                 0.40 
                 0.89 
               
               
                 pG16/pG29 
                 G91 
                 &gt;G86 
                 Membrane &amp; Cytoskeleton Proteins 
                 89 
                 0.91 
                 0.94 
                 0.96 
                 0.52 
                 1.79 
               
               
                 pG16 
                 G92 
                   
                 Protein binding, glut metab., OLIG (?) 
                 93 
                 0.14 
                 0.29 
                 1.49 
                 0.88 
                 2.54 
               
               
                   
                 G93 
                   
                 Regulation of Transcription, EGRs 
                 20 
                 0.75 
                 0.91 
                 0.93 
                 0.59 
                 1.45 
               
               
                 G21 
                 G94 
                 &gt;G89 &gt; G78 
                 Neural Genes 
                 168 
                 0.94 
                 0.94 
                 0.98 
                 0.59 
                 1.63 
               
               
                 G20 
                 G95 
                   
                 ?? = G20 
                 19 
                 0.25 
                 0.48 
                 1.39 
                 0.79 
                 2.44 
               
               
                 G12 
                 G96 
                 &gt;G87 &gt; G81 &gt; G75 
                 Interferon-induced Genes 
                 75 
                 0.82 
                 0.93 
                 1.04 
                 0.73 
                 1.48 
               
               
                 G27 
                 G97 
                 &gt;G76 
                 Spermatogenesis 
                 78 
                 0.09 
                 0.22 
                 1.38 
                 0.95 
                 2.00 
               
               
                 G28 
                 G98 
                   
                 HOX Genes 
                 21 
                 0.004 
                 0.07 
                 2.56 
                 1.34 
                 4.88 
               
               
                   
               
               
                 HR, hazard ratio; 
               
               
                 CI, confidence interval. 
               
               
                   a  corresponding clusters in G1 (S1); p, partial G1 (S1) cluster 
               
               
                   b p-value for the coefficient relative to the mean of the cluster in a multivariate Cox proportional hazards model adjusted for MGMT methylation status and age as additive independent risk factors (y~ β 1 meanCluster + β 2  MGMT + β 3  age) 
               
               
                   c FDR, False Discovery Rate 
               
               
                   d each continuous variable was scaled to have the interquartile range equal to 1 and median equal to 0. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Estimated Hazard Ratios (HR) for Treatment Effect in 
               
               
                 MGMT-methylated Patients at Different Expression Levels 
               
               
                 of G98 Multivariate Proportional Hazards Cox Model with 
               
               
                 N = 68. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 P-value 
               
               
                   
                   
                   
                   
                 Treatment 
               
               
                   
                 Expression Levels 
                 HR 
                 95% CI 
                 Interaction Term 
               
               
                   
               
               
                   
                 G98 
                   
                   
                 0.002 
               
               
                   
                   1st  quartile 
                 0.13 
                 0.05-0.37 
                   
               
               
                   
                 median 
                 0.25 
                 0.11-0.60 
                   
               
               
                   
                 3 rd  quartile 
                 0.47 
                 0.20-1.13 
               
               
                   
               
            
           
         
       
     
     The log-hazard function was defined as: 
         g ( t,X ,TMZ,MGMT,age,β)=ln [ h 0( t )]+β 1   X+β   2 TMZ+β 3 MGMT+β 4 age+β 5 ( X *TMZ)+β 6 (TMZ*MGMT)
 
     where X represents the expression level of G98 (summarized as the mean of the cluster), tmz is the dichotomous variable representing the regimen chemoradiotherapy versus radiotherapy alone, MGMT is a dichotomous variable representing MGMT promoter methylation status, age is a dichotomous variable (&gt;50 years at the time of randomization). 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 G28 versus G98 probesets 
               
            
           
           
               
               
               
               
               
            
               
                 G1 (S1) 
                 G1 (S4) 
                 Probeset 
                 RefSeq.Transcript ID 
                   
               
               
                   
               
               
                 G28 
                 — 
                 204121_at 
                 NM_006705 
                 GADD45G Chr: 9q22.1-q22.2 
               
               
                 G28 
                 G98 
                 1557051_s_at 
                 — 
                 — 
               
               
                 G28 
                 G98 
                 204362_at 
                 NM_003930 
                 SCAP2 Chr: 7p21-p15 
               
               
                 G28 
                 G98 
                 205522_at 
                 NM_014621 
                 HOXD4 Chr: 2q31.1 
               
               
                   
                   
                   
                 NM_004503 /// 
                   
               
               
                   
                   
                   
                 NM_014620 /// 
                   
               
               
                   
                   
                   
                 NM_153633 /// 
                   
               
               
                 G28 
                 G98 
                 206858_s_at 
                 NM_153693 
                 HOXC6 Chr: 12q13.3 
               
               
                 G28 
                 G98 
                 209905_at 
                 NM_152739 
                 HOXA9 Chr: 7p15-p14 
               
               
                   
                   
                   
                 NM_018951 /// 
                   
               
               
                 G28 
                 G98 
                 213150_at 
                 NM_153715 
                 HOXA10 Chr: 7p15-p14 
               
               
                 G28 
                 G98 
                 213844_at 
                 NM_019102 
                 HOXA5 Chr: 7p15-p14 
               
               
                 G28 
                 G98 
                 214651_s_at 
                 NM_152739 
                 HOXA9 Chr: 7p15-p14 
               
               
                 G28 
                 G98 
                 225639_at 
                 NM_003930 
                 SCAP2 Chr: 7p21-p15 
               
               
                 G28 
                 G98 
                 226582_at 
                 — 
                 LOC400043 chr12q13.13 
               
               
                   
                   
                   
                 XM_001716150 /// 
                   
               
               
                   
                   
                   
                 XM_374020 /// 
                   
               
               
                 G28 
                 G98 
                 228564_at 
                 XM_944366 
                 LOC375295 Chr: 2q31.2 
               
               
                 G28 
                 G98 
                 228642_at 
                 — 
                 — 
               
               
                 G28 
                 G98 
                 229400_at 
                 NM_002148 
                 HOXD10 Chr: 2q31.1 
               
               
                 G28 
                 G98 
                 231906_at 
                 NM_019558 
                 HOXD8 Chr: 2q31.1 
               
               
                   
                   
                   
                 NM_030661 /// 
                   
               
               
                   
                   
                   
                 NM_153631 /// 
                   
               
               
                 G28 
                 G98 
                 235521_at 
                 NM_153632 
                 HOXA3 Chr: 7p15-p14 
               
               
                 G28 
                 G98 
                 235753_at 
                 NM_006896 
                 HOXA7 chr7p15-p14 
               
               
                 G28 
                 G98 
                 238847_at 
                 — 
                 HOXD10 chr2q31.1 
               
               
                 G28 
                 G98 
                 239153_at 
                 — 
                 FLJ41747 chr12q13.13 
               
               
                 G28 
                 G98 
                 244521_at 
                 NM_173485 
                 — 
               
               
                 — 
                 G98 
                 204304_s_at 
                 NM_006017 
                 PROM1 Chr: 4p15.33 
               
               
                 — 
                 G98 
                 226863_at 
                 NM_001077710 
                 FAM110C chr2p25.3 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Mouse probe-sets used for GSEA in Krivtsov dataset 
               
               
                 Only most variant probe sets (sd &gt;0.5) were retained 
               
               
                 for GSEA 
               
               
                 G98 Mouse Homologues 
               
            
           
           
               
               
               
            
               
                 Probesets 
                 Gene.Title 
                 Gene.Symbol 
               
               
                   
               
               
                 1431475_a_at 
                 homeo box A10 
                 HoxA10 
               
               
                 1427433_s_at 
                 homeo box A3 
                 HoxA3 
               
               
                 1448926_at 
                 homeo box A5 
                 HoxA5 
               
               
                 1452421_at 
                 homeo box A3 
                 HoxA3 
               
               
                 1455626_at 
                 homeo box A9 
                 HoxA9 
               
               
                 1421579_at 
                 homeo box A9 
                 HoxA9 
               
               
                 1427454_at 
                 homeo box C6 
                 HoxC6 
               
               
                 1418879_at 
                 RIKEN cDNA 9030611O19 gene 
                 9030611O19Rik 
               
               
                 1418895_at 
                 src family associated 
                 Scap2 
               
               
                   
                 phosphoprotein 2 
                   
               
               
                 1419700_a_at 
                 prominin 1 
                 Prom1 
               
               
                 1449252_at 
                 RIKEN cDNA 9030611O19 gene 
                 9030611O19Rik 
               
               
                 1450209_at 
                 homeo box D4 
                 HoxD4 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Human probe-sets used for GSEA in Ross dataset 
               
               
                 Only most variant probe sets (sd &gt;0.5) were retained for GSEA 
               
               
                 G98 U133A Corresponding Probesets to U133Plus2.0 
               
            
           
           
               
               
               
            
               
                 Probesets 
                 Gene.Title 
                 Gene.Symbol 
               
               
                   
               
               
                 214651_s_at 
                 homeobox A9 
                 HOXA9 
               
               
                 213150_at 
                 homeobox A10 
                 HOXA10 
               
               
                 209905_at 
                 homeobox A9 
                 HOXA9 
               
               
                 213844_at 
                 homeobox A5 
                 HOXA5 
               
               
                 204362_at 
                 src family associated phosphoprotein 2 
                 SCAP2 
               
               
                 204304_s_at 
                 prominin 1 
                 PROM1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Gene Cluster G7 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 RefSeq. 
                 Chromosomal 
                   
                   
               
               
                 Probe Id 
                 Gene Symbol 
                 Transcript ID 
                 Location 
                 Comments 
                 Ref 
               
               
                   
               
               
                 1556499_s_at 
                 COL1A1 
                 NM_000088 
                 chr17q21.33 
                 Tumour endothelium marker 
                 
                   11 
                 
               
               
                 200700_s_at 
                 KDELR2 
                 NM_001100603 
                 chr7p22.1 
               
               
                   
                   
                 /// NM_006854 
               
               
                 200771_at 
                 LAMC1 
                 NM_002293 
                 chr1q31 
                 Basement membrane 
               
               
                 201438_at 
                 COL6A3 
                 NM_004369 /// 
                 chr2q37 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                   
                   
                 NM_057164 /// 
               
               
                   
                   
                 NM_057165 /// 
               
               
                   
                   
                 NM_057166 /// 
               
               
                   
                   
                 NM_057167 
               
               
                 201505_at 
                 LAMB1 
                 NM_002291 
                 chr7q22 
                 Basement membrane 
               
               
                 201744_s_at 
                 LUM 
                 NM_002345 
                 chr12q21.3-q22 
                 Angiogenesis 
                 
                   12 
                 
               
               
                 201852_x_at 
                 COL3A1 
                 NM_000090 
                 chr2q31 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 202007_at 
                 NID1 
                 NM_002508 
                 chr1q43 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 202112_at 
                 VWF 
                 NM_000552 
                 chr12p13.3 
                 Endothelial marker 
               
               
                 202202_s_at 
                 LAMA4 
                 NM_001105206 
                 chr6q21 
                 Basement membrane 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001105207 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001105208 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001105209 
               
               
                   
                   
                 /// NM_002290 
               
               
                 202291_s_at 
                 MGP 
                 NM_000900 
                 chr12p13.1-p12.3 
                 Endothelial marker 
                 
                   11 
                 
               
               
                 202310_s_at 
                 COL1A1 
                 NM_000088 
                 chr17q21.33 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 202375_at 
                 SEC24D 
                 NM_014822 
                 chr4q26 
               
               
                 202403_s_at 
                 COL1A2 
                 NM_000089 
                 chr7q22.1 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 202404_s_at 
                 COL1A2 
                 NM_000089 
                 chr7q22.1 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 202465_at 
                 PCOLCE 
                 NM_002593 
                 chr7q22 
               
               
                 202709_at 
                 FMOD 
                 NM_002023 
                 chr1q32 
               
               
                 202766_s_at 
                 FBN1 
                 NM_000138 
                 chr15q21.1 
                 Endothelial marker 
               
               
                 202878_s_at 
                 CD93 
                 NM_012072 
                 chr20p11.21 
               
               
                 202952_s_at 
                 ADAM12 
                 NM_003474 /// 
                 chr10q26.3 
                 Cell adhesion 
               
               
                   
                   
                 NM_021641 
               
               
                 202998_s_at 
                 LOXL2 
                 NM_002318 /// 
                 chr8p21.3-p21.2 
               
               
                   
                   
                 NM_004901 
               
               
                 203325_s_at 
                 COL5A1 
                 NM_000093 
                 chr9q34.2-q34.3 
               
               
                 203851_at 
                 IGFBP6 
                 NM_002178 
                 chr12q13 
                 Angiogenesis 
               
               
                 204017_at 
                 KDELR3 
                 NM_006855 /// 
                 chr22q13.1 
               
               
                   
                   
                 NM_016657 
               
               
                 204083_s_at 
                 TPM2 
                 NM_003289 /// 
                 chr9p13.2-p13.1 
               
               
                   
                   
                 NM_213674 
               
               
                 204114_at 
                 NID2 
                 NM_007361 
                 chr14q21-q22 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 204464_s_at 
                 EDNRA 
                 NM_001957 
                 chr4q31.23 
                 Patterning of blood vessels 
                 GO 
               
               
                 204677_at 
                 CDH5 
                 NM_001795 
                 chr16q22.1 
                 Endothelial marker 
               
               
                 204682_at 
                 LTBP2 
                 NM_000428 
                 chr14q24 
               
               
                 204844_at 
                 ENPEP 
                 NM_001977 
                 chr4q25 
                 Angiogenesis 
                 
                   13 
                 
               
               
                 205499_at 
                 SRPX2 
                 NM_014467 
                 chrXq21.33-q23 
               
               
                 205572_at 
                 ANGPT2 
                 NM_001118887 
                 chr8p23.1 
                 Angiogenesis 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001118888 
               
               
                   
                   
                 /// NM_001147 
               
               
                 207714_s_at 
                 SERPINH1 
                 NM_001235 
                 chr11q13.5 
               
               
                 208690_s_at 
                 PDLIM1 
                 NM_020992 
                 chr10q22-q26.3 
               
               
                 209156_s_at 
                 COL6A2 
                 NM_001849 /// 
                 chr21q22.3 
                 Endothelial marker 
               
               
                   
                   
                 NM_058174 /// 
               
               
                   
                   
                 NM_058175 
               
               
                 209596_at 
                 MXRA5 
                 NM_015419 
                 chrXp22.33 
               
               
                 210495_x_at 
                 FN1 
                 NM_002026 /// 
                 chr2q34 
                 Basement membrane 
               
               
                   
                   
                 NM_054034 /// 
               
               
                   
                   
                 NM_212474 /// 
               
               
                   
                   
                 NM_212475 /// 
               
               
                   
                   
                 NM_212476 /// 
               
               
                   
                   
                 NM_212478 /// 
               
               
                   
                   
                 NM_212482 
               
               
                 211148_s_at 
                 ANGPT2 
                 NM_001118887 
                 chr8p23.1 
                 Angiogenesis 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001118888 
               
               
                   
                   
                 /// NM_001147 
               
               
                 211161_s_at 
                 COL3A1 
                 NM_000090 
                 chr2q31 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 211343_s_at 
                 COL13A1 
                 NM_005203 /// 
                 chr10q22 
               
               
                   
                   
                 NM_080798 /// 
               
               
                   
                   
                 NM_080799 /// 
               
               
                   
                   
                 NM_080800 /// 
               
               
                   
                   
                 NM_080801 /// 
               
               
                   
                   
                 NM_080802 /// 
               
               
                   
                   
                 NM_080803 /// 
               
               
                   
                   
                 NM_080804 /// 
               
               
                   
                   
                 NM_080805 /// 
               
               
                   
                   
                 NM_080806 /// 
               
               
                   
                   
                 NM_080807 /// 
               
               
                   
                   
                 NM_080808 /// 
               
               
                   
                   
                 NM_080809 /// 
               
               
                   
                   
                 NM_080810 /// 
               
               
                   
                   
                 NM_080811 /// 
               
               
                   
                   
                 NM_080812 /// 
               
               
                   
                   
                 NM_080813 /// 
               
               
                   
                   
                 NM_080814 /// 
               
               
                   
                   
                 NM —   
               
               
                 211651_s_at 
                 LAMB1 
                 NM_002291 
                 chr7q22 
                 Basement membrane 
               
               
                 211719_x_at 
                 FN1 
                 NM_002026 /// 
                 chr2q34 
                 Basement membrane 
               
               
                   
                   
                 NM_054034 /// 
               
               
                   
                   
                 NM_212474 /// 
               
               
                   
                   
                 NM_212475 /// 
               
               
                   
                   
                 NM_212476 /// 
               
               
                   
                   
                 NM_212478 /// 
               
               
                   
                   
                 NM_212482 
               
               
                 211964_at 
                 COL4A2 
                 NM_001846 
                 chr13q34 
                 Glioma endothelial marker 
                 
                   14 
                 
               
               
                 211966_at 
                 COL4A2 
                 NM_001846 
                 chr13q34 
                 Glioma endothelial marker 
                 
                   14 
                 
               
               
                 211980_at 
                 COL4A1 
                 NM_001845 
                 chr13q34 
                 Glioma endothelial marker 
                 
                   14 
                 
               
               
                 211981_at 
                 COL4A1 
                 NM_001845 
                 chr13q34 
                 Glioma endothelial marker 
                 
                   14 
                 
               
               
                 212298_at 
                 NRP1 
                 NM_001024628 
                 chr10p12 
                 Angiogenesis 
                 
                   15 
                 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001024629 
               
               
                   
                   
                 /// NM_003873 
               
               
                 212364_at 
                 MYO1B 
                 NM_012223 
                 chr2q12-q34 
               
               
                 212464_s_at 
                 FN1 
                 NM_002026 /// 
                 chr2q34 
                 Basement membrane 
               
               
                   
                   
                 NM_054034 /// 
               
               
                   
                   
                 NM_212474 /// 
               
               
                   
                   
                 NM_212475 /// 
               
               
                   
                   
                 NM_212476 /// 
               
               
                   
                   
                 NM_212478 /// 
               
               
                   
                   
                 NM_212482 
               
               
                 212488_at 
                 COL5A1 
                 NM_000093 
                 chr9q34.2-q34.3 
               
               
                 212489_at 
                 COL5A1 
                 NM_000093 
                 chr9q34.2-q34.3 
               
               
                 213125_at 
                 OLFML2B 
                 NM_015441 
                 chr1q23.3 
               
               
                 213139_at 
                 SNAI2 
                 NM_003068 
                 chr8q11 
               
               
                 213790_at 
                 — 
                 — 
                 — 
               
               
                 214081_at 
                 PLXDC1 
                 NM_020405 
                 chr17q21.1 
               
               
                 215076_s_at 
                 COL3A1 
                 NM_000090 
                 chr2q31 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 216442_x_at 
                 FN1 
                 NM_002026 /// 
                 chr2q34 
                 Basement membrane 
               
               
                   
                   
                 NM_054034 /// 
               
               
                   
                   
                 NM_212474 /// 
               
               
                   
                   
                 NM_212475 /// 
               
               
                   
                   
                 NM_212476 /// 
               
               
                   
                   
                 NM_212478 /// 
               
               
                   
                   
                 NM_212482 
               
               
                 218729_at 
                 LXN 
                 NM_020169 
                 chr3q25.32 
               
               
                 219134_at 
                 ELTD1 
                 NM_022159 
                 chr1p33-p32 
               
               
                 219773_at 
                 NOX4 
                 NM_016931 
                 chr11q14.2-q21 
                 oxygen sensor activity 
                 
                   16 
                 
               
               
                 221729_at 
                 COL5A2 
                 NM_000393 
                 chr2q14-q32 
               
               
                 221730_at 
                 COL5A2 
                 NM_000393 
                 chr2q14-q32 
               
               
                 224833_at 
                 ETS1 
                 NM_005238 
                 chr11q23.3 
                 Angiogenesis 
                 
                   17 
                 
               
               
                 225681_at 
                 CTHRC1 
                 NM_138455 
                 chr8q22.3 
                 Vascular remodeling 
                 
                   18 
                 
               
               
                 225799_at 
                 MGC4677 /// 
                 XR_039885 /// 
                 chr2p11.2 /// chr2q13 
               
               
                   
                 LOC541471 
                 XR_039886 /// 
               
               
                   
                   
                 XR_042051 /// 
               
               
                   
                   
                 XR_042052 
               
               
                 226311_at 
                 — 
                 — 
                 — 
               
               
                 226731_at 
                 PELO 
                 NM_015946 
                 chr5q11.2 
               
               
                 226777_at 
                 — 
                 — 
                 — 
               
               
                 226804_at 
                 FAM20A 
                 NM_017565 
                 chr17q24.2 
               
               
                 227628_at 
                 LOC493869 
                 NM_001008397 
                 chr5q11.2 
               
               
                 228776_at 
                 GJA7 
                 NM_001080383 
                 chr17q21.31 
               
               
                   
                   
                 /// NM_005497 
               
               
                 229218_at 
                 COL1A2 
                 NM_000089 
                 chr7q22.1 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 230061_at 
                 TM4SF18 
                 NM_138786 
                 chr3q25.1 
               
               
                 232458_at 
                 COL3A1 
                 NM_000090 
                 chr2q31 
                 Tumor endothelium marker 
                 
                   11 
                 
               
               
                 236034_at 
                 — 
                 NM_001118887 
                 — 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001118888 
               
               
                   
                   
                 /// NM_001147 
               
               
                 237261_at 
                 — 
                 NM_001118887 
                 — 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001118888 
               
               
                   
                   
                 /// NM_001147 
               
               
                 241981_at 
                 FAM20A 
                 NM_017565 
                 chr17q24.2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Gene Cluster G13 
               
            
           
           
               
               
               
               
            
               
                   
                 Gene 
                   
                 Chromosomal 
               
               
                 Probe Id 
                 Symbol 
                 RefSeq.Transcript.ID 
                 Location 
               
               
                   
               
               
                 1555385_at 
                 B4GALNT1 
                 NM_001478 
                 chr12q13.3 
               
               
                 1568706_s_at 
                 AVIL 
                 NM_006576 
                 chr12q14.1 
               
               
                   
                   
                 NM_001017956 /// 
                   
               
               
                   
                   
                 NM_001017957 /// 
                   
               
               
                   
                   
                 NM_001017958 /// 
                   
               
               
                 200714_x_at 
                 OS9 
                 NM_006812 
                 chr12q13 
               
               
                 201131_s_at 
                 CDH1 
                 NM_004360 
                 chr16q22.1 
               
               
                 202246_s_at 
                 CDK4 
                 NM_000075 
                 chr12q14 
               
               
                 203226_s_at 
                 TSPAN31 
                 NM_005981 
                 chr12q13.3 
               
               
                 203227_s_at 
                 TSPAN31 
                 NM_005981 
                 chr12q13.3 
               
               
                   
                   
                 NM_005371 /// 
                   
               
               
                 204027_s_at 
                 METTL1 
                 NM_023033 
                 chr12q13 
               
               
                   
                   
                 NM_002392 /// 
                   
               
               
                   
                   
                 NM_006878 /// 
                   
               
               
                   
                   
                 NM_006879 /// 
                   
               
               
                   
                   
                 NM_006881 /// 
                   
               
               
                 205386_s_at 
                 MDM2 
                 NM_006882 
                 chr12q14.3-q15 
               
               
                 205539_at 
                 AVIL 
                 NM_006576 
                 chr12q14.1 
               
               
                 205676_at 
                 CYP27B1 
                 NM_000785 
                 chr12q13.1-q13.3 
               
               
                   
                   
                 NM_001005502 /// 
                   
               
               
                   
                   
                 NM_001874 /// 
                   
               
               
                 206100_at 
                 CPM 
                 NM_198320 
                 chr12q14.3 
               
               
                 206435_at 
                 B4GALNT1 
                 NM_001478 
                 chr12q13.3 
               
               
                   
                   
                 NM_002392 /// 
                   
               
               
                   
                   
                 NM_006878 /// 
                   
               
               
                   
                   
                 NM_006879 /// 
                   
               
               
                   
                   
                 NM_006881 /// 
                   
               
               
                 211832_s_at 
                 MDM2 
                 NM_006882 
                 chr12q14.3-q15 
               
               
                 212656_at 
                 TSFM 
                 NM_005726 
                 chr12q13-q14 
               
               
                 213861_s_at 
                 FAM119B 
                 NM_015433 /// 
                 chr12q14.1 
               
               
                   
                   
                 NM_206914 
                   
               
               
                 214331_at 
                 TSFM 
                 NM_005726 
                 chr12q13-q14 
               
               
                 214332_s_at 
                 TSFM 
                 NM_005726 
                 chr12q13-q14 
               
               
                 214951_at 
                 SLC26A10 
                 NM_133489 
                 chr12q13 
               
               
                   
                   
                 NM_001017956 /// 
                   
               
               
                   
                   
                 NM_001017957 /// 
                   
               
               
                   
                   
                 NM_001017958 /// 
                   
               
               
                 215399_s_at 
                 OS9 
                 NM_006812 
                 chr12q13 
               
               
                   
                   
                 NM_002392 /// 
                   
               
               
                   
                   
                 NM_006878 /// 
                   
               
               
                   
                   
                 NM_006879 /// 
                   
               
               
                   
                   
                 NM_006881 /// 
                   
               
               
                 217373_x_at 
                 MDM2 
                 NM_006882 
                 chr12q14.3-q15 
               
               
                 217542_at 
                 CPM 
                 — 
                 chr12q14.3 
               
               
                 218768_at 
                 NUP107 
                 NM_020401 
                 chr12q15 
               
               
                 224489_at 
                 KIAA1267 
                 NM_015443 
                 chr17q21.31 
               
               
                 225160_x_at 
                 MGC5370 
                 — 
                 chr12q14.3 
               
               
                 226454_at 
                 MARCH9 
                 NM_138396 
                 chr12q14.1 
               
               
                 226546_at 
                 — 
                 — 
                 — 
               
               
                 227678_at 
                 XRCC6BP1 
                 NM_033276 
                 chr12q14.1 
               
               
                 229711_s_at 
                 MGC5370 
                 — 
                 chr12q14.3 
               
               
                 229917_at 
                 — 
                 — 
                 — 
               
               
                 230001_at 
                 MARCH9 
                 NM_138396 
                 chr12q14.1 
               
               
                   
                   
                 NM_001005502 /// 
                   
               
               
                   
                   
                 NM_001874 /// 
                   
               
               
                 235019_at 
                 CPM 
                 NM_198320 
                 chr12q14.3 
               
               
                   
                   
                 NM_001005502 /// 
                   
               
               
                   
                   
                 NM_001874 /// 
                   
               
               
                 235706_at 
                 CPM 
                 NM_198320 
                 chr12q14.3 
               
               
                 235721_at 
                 DTX3 
                 NM_178502 
                 chr12q13.3 
               
               
                 238733_at 
                 CPM 
                 — 
                 chr12q14.3 
               
               
                 238999_at 
                 AVIL 
                 — 
                 chr12q14.1 
               
               
                   
                   
                 NM_001005502 /// 
                   
               
               
                 241765_at 
                 CPM 
                 NM_001874 /// 
                 chr12q14.3 
               
               
                   
                   
                 NM_198320 
                   
               
               
                   
                   
                 NM_001102450 /// 
                   
               
               
                 244675_at 
                 RGS8 
                 NM_033345 
                 chr1q25 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Gene Cluster G14 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 Chromosomal 
                   
                   
               
               
                 Probe Id 
                 Gene Symbol 
                 RefSeq. Transcript. ID 
                 Location 
                 Comments 
                 Ref. 
               
               
                   
               
               
                 203180_at 
                 ALDH1A3 
                 NM_000693 
                 chr15q26.3 
                 Differentiation of stem cells 
                 
                   19 
                 
               
               
                 203434_s_at 
                 MME 
                 NM_000902 /// 
                 chr3q25.1-q25.2 
               
               
                   
                   
                 NM_007287 /// 
               
               
                   
                   
                 NM_007288 /// 
               
               
                   
                   
                 NM_007289 
               
               
                 204776_at 
                 THBS4 
                 NM_003248 
                 chr5q13 
               
               
                 205430_at 
                 BMP5 
                 NM_021073 
                 chr6p12.1 
                 Differentiation of stem cells 
                 
                   20 
                 
               
               
                 205431_s_at 
                 BMP5 
                 NM_021073 
                 chr6p12.1 
                 Differentiation of stem cells 
                 
                   20 
                 
               
               
                 205619_s_at 
                 MEOX1 
                 NM_001040002 /// 
                 chr17q21 
                 Regulator of BMPs 
                 
                   21 
                 
               
               
                   
                   
                 NM_004527 /// 
               
               
                   
                   
                 NM_013999 
               
               
                 205713_s_at 
                 COMP 
                 NM_000095 
                 chr19p13.1 
               
               
                 205848_at 
                 GAS2 
                 NM_005256 /// 
                 chr11p14.3-p15.2 
                 Apoptosis 
               
               
                   
                   
                 NM_177553 
               
               
                 212414_s_at 
                 SEPT6 /// N-PAC 
                 NM_015129 /// 
                 chrXq24 /// chr16p13.3 
               
               
                   
                   
                 NM_032569 /// 
               
               
                   
                   
                 NM_145799 /// 
               
               
                   
                   
                 NM_145800 /// 
               
               
                   
                   
                 NM_145802 
               
               
                 213456_at 
                 SOSTDC1 
                 NM_015464 
                 chr7p21.1 
                 Regulator of BMPs 
                 
                   22 
                 
               
               
                 217525_at 
                 OLFML1 
                 NM_198474 
                 chr11p15.4 
               
               
                 218499_at 
                 RP6-213H19.1 
                 NM_001042452 /// 
                 chrXq26.2 
               
               
                   
                   
                 NM_001042453 /// 
               
               
                   
                   
                 NM_016542 
               
               
                 219837_s_at 
                 CYTL1 
                 NM_018659 
                 chr4p16-p15 
               
               
                 220014_at 
                 PRR16 
                 NM_016644 
                 chr5q23.1 
                 Mesenchymal stem cell marker 
                 
                   23 
                 
               
               
                 220065_at 
                 TNMD 
                 NM_022144 
                 chrXq21.33-q23 
               
               
                 226834_at 
                 — 
                 — 
                 — 
               
               
                 226930_at 
                 FNDC1 
                 NM_032532 
                 chr6q25 
               
               
                 227070_at 
                 GLT8D2 
                 NM_031302 
                 chr12q 
               
               
                 227850_x_at 
                 CDC42EP5 
                 NM_145057 
                 chr19q13.42 
               
               
                 229839_at 
                 SCARA5 
                 NM_173833 
                 chr8p21.1 
               
               
                 231766_s_at 
                 COL12A1 
                 NM_004370 /// 
                 chr6q12-q13 
               
               
                   
                   
                 NM_080645 
               
               
                 232090_at 
                 DNM3 
                 XM_001715447 /// 
                 chr1q24.3 
               
               
                   
                   
                 XM_001718852 /// 
               
               
                   
                   
                 XM_001718912 
               
               
                 235944_at 
                 HMCN1 
                 NM_031935 
                 chr1q25.3-q31.1 
               
               
                 236035_at 
                 — 
                 — 
                 — 
               
               
                 239468_at 
                 MKX 
                 NM_173576 
                 chr10p12.1 
                 Homeobox gene 
                 
                   24 
                 
               
               
                 244885_at 
                 — 
                 — 
                 — 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Gene Cluster G18 
               
            
           
           
               
               
               
               
            
               
                   
                 Gene 
                   
                 Chromosomal 
               
               
                 Probe Id 
                 Symbol 
                 RefSeq.Transcript.ID 
                 Location 
               
               
                   
               
               
                 202800_at 
                 SLC1A3 
                 NM_004172 
                 chr5p13 
               
               
                 203723_at 
                 ITPKB 
                 NM_002221 
                 chr1q42.13 
               
               
                 204041_at 
                 MAOB 
                 NM_000898 
                 chrXp11.23 
               
               
                 204363_at 
                 F3 
                 NM_001993 
                 chr1p22-p21 
               
               
                 205363_at 
                 BBOX1 
                 NM_003986 
                 chr11p14.2 
               
               
                   
                   
                 NM_001390 /// 
                   
               
               
                   
                   
                 NM_001391 /// 
                   
               
               
                   
                   
                 NM_001392 /// 
                   
               
               
                   
                   
                 NM_032975 /// 
                   
               
               
                   
                   
                 NM_032978 /// 
                   
               
               
                   
                   
                 NM_032979 /// 
                   
               
               
                   
                   
                 NM_032980 /// 
                   
               
               
                 205741_s_at 
                 DTNA 
                 NM_032981 
                 chr18q12 
               
               
                 206022_at 
                 NDP 
                 NM_000266 
                 chrXp11.4 
               
               
                 207443_at 
                 NR2E1 
                 NM_003269 
                 chr6q21 
               
               
                 207455_at 
                 P2RY1 
                 NM_002563 
                 chr3q25.2 
               
               
                 209301_at 
                 CA2 
                 NM_000067 
                 chr8q22 
               
               
                 209921_at 
                 SLC7A11 
                 NM_014331 
                 chr4q28-q32 
               
               
                   
                   
                 NM_001650 /// 
                   
               
               
                 210066_s_at 
                 AQP4 
                 NM_004028 
                 chr18q11.2-q12.1 
               
               
                   
                   
                 NM_001650 /// 
                   
               
               
                 210067_at 
                 AQP4 
                 NM_004028 
                 chr18q11.2-q12.1 
               
               
                   
                   
                 NM_001650 /// 
                   
               
               
                 210068_s_at 
                 AQP4 
                 NM_004028 
                 chr18q11.2-q12.1 
               
               
                   
                   
                 NM_001650 /// 
                   
               
               
                 210906_x_at 
                 AQP4 
                 NM_004028 
                 chr18q11.2-q12.1 
               
               
                   
                   
                 NM_015166 /// 
                   
               
               
                 213395_at 
                 MLC1 
                 NM_139202 
                 chr22q13.33 
               
               
                   
                   
                 NM_015230 /// 
                   
               
               
                 213618_at 
                 CENTD1 
                 NM_139182 
                 chr4p14 
               
               
                 217678_at 
                 SLC7A11 
                 NM_014331 
                 chr4q28-q32 
               
               
                 223605_at 
                 SLC25A18 
                 NM_031481 
                 chr22q11.2 
               
               
                 226189_at 
                 ITGB8 
                 NM_002214 
                 chr7p15.3 
               
               
                   
                   
                 NM_001650 /// 
                   
               
               
                 226228_at 
                 AQP4 
                 NM_004028 
                 chr18q11.2-q12.1 
               
               
                   
                   
                 NM_001390 /// 
                   
               
               
                   
                   
                 NM_001391 /// 
                   
               
               
                   
                   
                 NM_001392 /// 
                   
               
               
                   
                   
                 NM_032975 /// 
                   
               
               
                   
                   
                 NM_032978 /// 
                   
               
               
                   
                   
                 NM_032979 /// 
                   
               
               
                   
                   
                 NM_032980 /// 
                   
               
               
                 227084_at 
                 DTNA 
                 NM_032981 
                 chr18q12 
               
               
                 231925_at 
                 P2RY1 
                 — 
                 chr3q25.2 
               
               
                   
                   
                 NM_000280 /// 
                   
               
               
                 235795_at 
                 PAX6 
                 NM_001604 
                 chr11p13 
               
               
                 238003_at 
                 FLJ25530 
                 NM_152722 
                 chr11q24.2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Gene Cluster G24 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 RefSeq. 
                 Chromosomal 
                   
                   
               
               
                 Probe Id 
                 Gene Symbol 
                 Transcript ID 
                 Location 
                 Comments 
                 Ref 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1552316_a_at 
                 GIMAP1 
                 NM_130759 
                 chr7q36.1 
                   
                   
               
               
                 1552365_at 
                 SCIN 
                 NM_001112706 
                 chr7p21.3 
               
               
                   
                   
                 /// NM_033128 
               
               
                 1552367_a_at 
                 SCIN 
                 NM_001112706 
                 chr7p21.3 
               
               
                   
                   
                 /// NM_033128 
               
               
                 1552386_at 
                 C5orf29 
                 NM_152687 
                 chr5q11.2 
               
               
                 1552807_a_at 
                 SIGLEC10 
                 NM_033130 
                 chr19q13.3 
               
               
                 1554899_s_at 
                 FCER1G 
                 NM_004106 
                 chr1q23 
                 M2 Marker 
                 
                   25 
                 
               
               
                 1555349_a_at 
                 ITGB2 
                 NM_000211 
                 chr21q22.3 
                 Macrophage 
               
               
                   
                   
                   
                   
                 markers 
               
               
                 1555728_a_at 
                 MS4A4A 
                 NM_024021 /// 
                 chr11q12 
               
               
                   
                   
                 NM_148975 
               
               
                 201137_s_at 
                 HLA-DPB1 
                 NM_002121 
                 chr6p21.3 
                   
                 
                   25 
                 
               
               
                 201422_at 
                 IFI30 
                 NM_005027 /// 
                 chr19p13.1 
               
               
                   
                   
                 NM_006332 
               
               
                 201487_at 
                 CTSC 
                 NM_001114173 
                 chr11q14.1-q14.3 
                 M2 Marker 
                 
                   26 
                 
               
               
                   
                   
                 /// NM_001814 /// 
               
               
                   
                   
                 NM_148170 
               
               
                 201631_s_at 
                 IER3 
                 NM_003897 
                 chr6p21.3 
               
               
                 201721_s_at 
                 LAPTM5 
                 NM_006762 
                 chr1p34 
               
               
                 201743_at 
                 CD14 
                 NM_000591 /// 
                 chr5q22-q32|5q31.1 
                 Innate immunity 
               
               
                   
                   
                 NM_001040021 
               
               
                 202546_at 
                 VAMP8 
                 NM_003761 
                 chr2p12-p11. 
               
               
                 202803_s_at 
                 ITGB2 
                 NM_000211 
                 chr21q22.3 
               
               
                 202833_s_at 
                 SERPINA1 
                 NM_000295 /// 
                 chr14q32.1 
               
               
                   
                   
                 NM_001002235 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001002236 
               
               
                 202901_x_at 
                 CTSS 
                 NM_004079 
                 chr1q21 
                 M2 Marker 
                 
                   26 
                 
               
               
                 202902_s_at 
                 CTSS 
                 NM_004079 
                 chr1q21 
                 M2 Marker 
                 
                   26 
                 
               
               
                 202917_s_at 
                 S100A8 
                 NM_002964 
                 chr1q21 
               
               
                 202953_at 
                 C1QB 
                 NM_000491 
                 chr1p36.12 
                 M2 Marker 
                 
                   27 
                 
               
               
                 202957_at 
                 HCLS1 
                 NM_005335 
                 chr3q13 
               
               
                 203104_at 
                 CSF1R 
                 NM_005211 
                 chr5q33-q35 
               
               
                 203290_at 
                 HLA-DQA1 
                 NM_002122 /// 
                 chr6p21.3 
               
               
                   
                   
                 XM_001722240 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001723439 
               
               
                 203305_at 
                 F13A1 
                 NM_000129 
                 chr6p25.3-p24.3 
                 M2 Marker 
                 
                   26 
                 
               
               
                 203416_at 
                 CD53 
                 NM_000560 /// 
                 chr1p13 
                 Macrophage 
               
               
                   
                   
                 NM_001040033 
                   
                 markers 
               
               
                 203535_at 
                 S100A9 
                 NM_002965 
                 chr1q21 
               
               
                 203561_at 
                 FCGR2A 
                 NM_021642 
                 chr1q23 
               
               
                 203645_s_at 
                 CD163 
                 NM_004244 /// 
                 chr12p13.3 
                 M2 Marker 
                 
                   28 
                 
               
               
                   
                   
                 NM_203416 
               
               
                 203665_at 
                 HMOX1 
                 NM_002133 
                 chr22q12|22q13.1 
               
               
                 204006_s_at 
                 FCGR3A /// 
                 NM_000569 /// 
                 chr1q23 
               
               
                   
                 FCGR3B 
                 NM_000570 
               
               
                 204007_at 
                 FCGR3B 
                 NM_000570 
                 chr1q23 
               
               
                 204122_at 
                 TYROBP 
                   
                 chr19q13.1 
                 Innate immunity 
               
               
                 204150_at 
                 STAB1 
                 NM_015136 
                 chr3p21.1 
                 M2 Marker 
                 
                   29 
                 
               
               
                 204174_at 
                 ALOX5AP 
                 NM_001629 
                 chr13q12 
                 M2 Marker 
                 
                   25 
                 
               
               
                 204232_at 
                 FCER1G 
                 NM_004106 
                 chr1q23 
                 M2 Marker 
                 
                   25 
                 
               
               
                 204416_x_at 
                 APOC1 
                 NM_001645 
                 chr19q13.2 
               
               
                 204430_s_at 
                 SLC2A5 
                 NM_003039 
                 chr1p36.2 
               
               
                 204438_at 
                 MRC1 /// MRC1L1 
                 NM_001009567 
                 chr10p12.33 
                 M2 Marker 
                 
                   30 
                 
               
               
                   
                   
                 /// NM_002438 
               
               
                 204446_s_at 
                 ALOX5 
                 NM_000698 
                 chr10q11.2 
                 M2 Marker 
                 25 
               
               
                 204563_at 
                 SELL 
                 NM_000655 
                 chr1q23-q25 
               
               
                 204670_x_at 
                 HLA-DRB1 
                 NM_001023561 
                 chr6p21.3 
                   
                 25 
               
               
                   
                   
                 /// NM_002123 /// 
               
               
                   
                   
                 NM_002124 /// 
               
               
                   
                   
                 NM_002125 /// 
               
               
                   
                   
                 NM_002934 /// 
               
               
                   
                   
                 NM_021983 /// 
               
               
                   
                   
                 NM_022555 /// 
               
               
                   
                   
                 NR_003937 /// 
               
               
                   
                   
                 XM_001124749 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713857 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713867 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714067 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714074 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001718754 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001719473 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001720834 
               
               
                   
                   
                 /// XM_0 
               
               
                 204787_at 
                 VSIG4 
                 NM_001100431 
                 chrXq12-q13.3 
               
               
                   
                   
                 /// NM_007268 
               
               
                 204834_at 
                 FGL2 
                 NM_006682 
                 chr7q11.23 
               
               
                 204959_at 
                 MNDA 
                 NM_002432 
                 chr1q22 
               
               
                 204971_at 
                 CSTA 
                 NM_005213 
                 chr3q21 
               
               
                 205027_s_at 
                 MAP3K8 
                 NM_005204 
                 chr10p11.23 
               
               
                 205119_s_at 
                 FPR1 
                 NM_002029 
                 chr19q13.4 
               
               
                 205681_at 
                 BCL2A1 
                 NM_001114735 
                 chr15q24.3 
               
               
                   
                   
                 /// NM_004049 
               
               
                 205786_s_at 
                 ITGAM 
                 NM_000632 
                 chr16p11.2 
               
               
                 205890_s_at 
                 UBD 
                 NM_001470 /// 
                 chr6p21.3 
               
               
                   
                   
                 NM_006398 /// 
               
               
                   
                   
                 NM_021903 /// 
               
               
                   
                   
                 NM_021904 /// 
               
               
                   
                   
                 NM_021905 
               
               
                 205898_at 
                 CX3CR1 
                 NM_001337 
                 chr3p21|3p21.3 
               
               
                 205997_at 
                 ADAM28 
                 NM_014265 /// 
                 chr8p21.2 
               
               
                   
                   
                 NM_021777 
               
               
                 206111_at 
                 HLA-DQB1 /// HLA- 
                 NM_001023561 
                 chr14q24-q31 
               
               
                   
                 DQB2 /// HLA- 
                 /// NM_002123 /// 
               
               
                   
                 DRB1 /// HLA-DRB2 
                 NM_002124 /// 
               
               
                   
                 /// HLA-DRB3 /// 
                 NM_002125 /// 
               
               
                   
                 HLA-DRB4 /// HLA- 
                 NM_002934 /// 
               
               
                   
                 DRB5 
                 NM_021983 /// 
               
               
                   
                   
                 NM_022555 /// 
               
               
                   
                   
                 NR_003937 /// 
               
               
                   
                   
                 XM_001124749 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713857 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713867 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714067 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714074 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001718754 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001719473 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001720834 
               
               
                   
                   
                 /// XM_0 
               
               
                 206420_at 
                 IGSF6 
                 NM_005849 
                 chr16p12-p13 
               
               
                 206584_at 
                 LY96 
                 NM_015364 
                 chr8q21.11 
               
               
                 207655_s_at 
                 BLNK 
                 NM_001114094 
                 chr10q23.2-q23.33 
               
               
                   
                   
                 /// NM_013314 
               
               
                 208018_s_at 
                 HCK 
                 NM_002110 
                 chr20q11-q12 
               
               
                 208146_s_at 
                 CPVL 
                 NM_019029 /// 
                 chr7p15-p14 
               
               
                   
                   
                 NM_031311 
               
               
                 208306_x_at 
                 HLA-DRB1 
                 NM_002124 
                 chr6p21.3 
                   
                 25 
               
               
                 208894_at 
                 HLA-DRA 
                 NM_019111 
                 chr6p21.3 
                   
                 25 
               
               
                 208944_at 
                 TGFBR2 
                 NM_001024847 
                 chr3p22 
                   
                 31 
               
               
                   
                   
                 /// NM_003242 
               
               
                 209312_x_at 
                 HLA-DRB1 
                 NM_001023561 
                 chr6p21.3 
                   
                 25 
               
               
                   
                   
                 /// NM_002123 /// 
               
               
                   
                   
                 NM_002124 /// 
               
               
                   
                   
                 NM_002125 /// 
               
               
                   
                   
                 NM_002934 /// 
               
               
                   
                   
                 NM_021983 /// 
               
               
                   
                   
                 NM_022555 /// 
               
               
                   
                   
                 NR_003937 /// 
               
               
                   
                   
                 XM_001124749 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713857 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713867 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714067 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714074 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001718754 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001719473 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001720834 
               
               
                   
                   
                 /// XM_0 
               
               
                 209619_at 
                 CD74 
                 NM_001025158 
                 chr5q32 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001025159 
               
               
                   
                   
                 /// NM_004355 
               
               
                 209823_x_at 
                 HLA-DQB1 
                 NM_002123 /// 
                 chr6p21.3 
                   
                 25 
               
               
                   
                   
                 XM_001722253 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001723447 
               
               
                 210176_at 
                 TLR1 
                 NM_003263 
                 chr4p14 
                 Innate immunity 
               
               
                 210314_x_at 
                 TNFSF13 /// 
                 NM_003808 
                 chr17p13.1 
               
               
                   
                 TNFSF12-TNFSF13 
                 /// 
               
               
                   
                   
                 NM_172087 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_172088 
               
               
                 210982_s_at 
                 HLA-DRA 
                 NM_019111 
                 chr6p21.3 
                   
                 25 
               
               
                 211429_s_at 
                 SERPINA1 
                 NM_000295 /// 
                 chr14q32.1 
               
               
                   
                   
                 NM_001002235 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001002236 
               
               
                 211654_x_at 
                 HLA-DQB1 /// 
                 NM_002123 /// 
                 chr6p21.3 
               
               
                   
                 LOC650557 
                 XM_001722253 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001723447 
               
               
                 211656_x_at 
                 HLA-DQB1 
                 NM_002123 /// 
                 chr6p21.3 
                   
                 25 
               
               
                   
                   
                 XM_001722253 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001723447 
               
               
                 211742_s_at 
                 EVI2B 
                 NM_006495 
                 chr17q11.2 
               
               
                 211990_at 
                 HLA-DPA1 
                 NM_033554 
                 chr6p21.3 
                   
                 25 
               
               
                 211991_s_at 
                 HLA-DPA1 
                 NM_033554 
                 chr6p21.3 
                   
                 25 
               
               
                 212543_at 
                 AIM1 
                 NM_001624 
                 chr6q21 
               
               
                 212588_at 
                 PTPRC 
                 NM_002838 /// 
                 chr1q31-q32 
                 Macrophage 
               
               
                   
                   
                 NM_080921 /// 
                   
                 markers 
               
               
                   
                   
                 NM_080922 /// 
               
               
                   
                   
                 NM_080923 
               
               
                 212671_s_at 
                 HLA-DQA1 /// HLA- 
                 NM_002122 /// 
                 chr6p21.3 
                   
                 25 
               
               
                   
                 DQA2 
                 NM_020056 /// 
               
               
                   
                   
                 XM_001722240 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001723439 
               
               
                 212998_x_at 
                 HLA-DQB1 
                 NM_001023561 
                 chr6p21.3 
                   
                 25 
               
               
                   
                   
                 /// NM_002123 /// 
               
               
                   
                   
                 NM_002124 /// 
               
               
                   
                   
                 NM_002125 /// 
               
               
                   
                   
                 NM_002934 /// 
               
               
                   
                   
                 NM_021983 /// 
               
               
                   
                   
                 NM_022555 /// 
               
               
                   
                   
                 NR_003937 /// 
               
               
                   
                   
                 XM_001124749 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713857 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713867 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714067 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714074 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001718754 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001719473 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001720834 
               
               
                   
                   
                 /// XM_0 
               
               
                 213537_at 
                 HLA-DPA1 
                 NM_033554 
                 chr6p21.3 
                   
                 25 
               
               
                 213566_at 
                 RNASE6 
                 NM_005615 
                 chr14q11.2 
               
               
                 214467_at 
                 GPR65 
                 NM_003608 
                 chr14q31-q32.1 
               
               
                 214511_x_at 
                 FCGR1A /// 
                 NM_001004340 
                 chr1q21.2-q21.3 
               
               
                   
                   
                 /// 
                 /// 
               
               
                   
                   
                 NM_001017986 
                 chr1p11.2 
               
               
                 214770_at 
                 MSR1 
                 NM_002445 /// 
                 chr8p22 
                 M2 Marker 
                 25 
               
               
                   
                   
                 NM_138715 /// 
               
               
                   
                   
                 NM_138716 
               
               
                 215049_x_at 
                 CD163 
                 NM_004244 /// 
                 chr12p13.3 
                 M2 Marker 
                 28 
               
               
                   
                   
                 NM_203416 
               
               
                 215193_x_at 
                 HLA-DRB1 
                 NM_001023561 
                 chr6p21.3 
                   
                 
                   25 
                 
               
               
                   
                   
                 /// NM_002123 /// 
               
               
                   
                   
                 NM_002124 /// 
               
               
                   
                   
                 NM_002125 /// 
               
               
                   
                   
                 NM_002934 /// 
               
               
                   
                   
                 NM_021983 /// 
               
               
                   
                   
                 NM_022555 /// 
               
               
                   
                   
                 NR_003937 /// 
               
               
                   
                   
                 XM_001124749 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713857 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713867 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714067 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714074 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001718754 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001719473 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001720834 
               
               
                   
                   
                 /// XM_0 
               
               
                 216233_at 
                 CD163 
                 NM_004244 /// 
                 chr12p13.3 
                 M2 Marker 
                 
                   28 
                 
               
               
                   
                   
                 NM_203416 
               
               
                 216950_s_at 
                 FCGR1A 
                 NM_000566 
                 chr1q21.2-q21.3 
               
               
                 217388_s_at 
                 KYNU 
                 NM_001032998 
                 chr2q22.2 
               
               
                   
                   
                 /// NM_003937 
               
               
                 217478_s_at 
                 HLA-DMA 
                 NM_006120 
                 chr6p21.3 
                   
                 
                   25 
                 
               
               
                 217767_at 
                 C3 /// LOC653879 
                 NM_000064 
                 chr19p13.3-p13.2 
                 Innate immunity 
               
               
                 217983_s_at 
                 RNASET2 
                 NM_003730 
                 chr6q27 
               
               
                 218232_at 
                 C1QA 
                 NM_015991 
                 chr1p36.12 
                 M2 Marker 
                 
                   27 
                 
               
               
                 218854_at 
                 SART2 
                 NM_001080976 
                 chr6q22 
               
               
                   
                   
                 /// NM_013352 
               
               
                 219386_s_at 
                 SLAMF8 
                 NM_020125 
                 chr1q23.2 
               
               
                 219607_s_at 
                 MS4A4A 
                 NM_024021 /// 
                 chr11q12 
               
               
                   
                   
                 NM_148975 
               
               
                 219666_at 
                 MS4A6A 
                 NM_022349 /// 
                 chr11q12.1 
               
               
                   
                   
                 NM_152851 /// 
               
               
                   
                   
                 NM_152852 
               
               
                 219890_at 
                 CLEC5A 
                 NM_013252 
                 chr7q33 
               
               
                 220005_at 
                 P2RY13 
                 NM_023914 /// 
                 chr3q24 
               
               
                   
                   
                 NM_176894 
               
               
                 220146_at 
                 TLR7 
                 NM_016562 
                 chrXp22.3 
                 Innate immunity 
               
               
                 220330_s_at 
                 SAMSN1 
                 NM_022136 
                 chr21q11 
               
               
                 220491_at 
                 HAMP 
                 NM_021175 
                 chr19q13.1 
                 Innate immunity 
               
               
                 220532_s_at 
                 LR8 
                 NM_001101311 
                 chr7q36.1 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001101312 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001101313 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001101314 
               
               
                   
                   
                 /// NM_014020 
               
               
                 221210_s_at 
                 NPL 
                 NM_030769 
                 chr1q25 
               
               
                 221491_x_at 
                 HLA-DRB1 /// HLA- 
                 NM_001023561 
                 chr6p21.3 
                   
                 
                   25 
                 
               
               
                   
                 DRB3 /// HLA-DRB4 
                 /// NM_002123 /// 
               
               
                   
                 /// H LA-DRB5 
                 NM_002124 /// 
               
               
                   
                   
                 NM_002125 /// 
               
               
                   
                   
                 NM_002934 /// 
               
               
                   
                   
                 NM_021983 /// 
               
               
                   
                   
                 NM_022555 /// 
               
               
                   
                   
                 NR_003937 /// 
               
               
                   
                   
                 XM_001124749 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713857 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001713867 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714067 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001714074 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001718754 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001719473 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 XM_001720834 
               
               
                   
                   
                 /// XM_0 
               
               
                 221698_s_at 
                 CLEC7A 
                 NM_022570 /// 
                 chr12p13.2 
                 M2 Marker 
                 
                   32 
                 
               
               
                   
                   
                 NM_197947 /// 
               
               
                   
                   
                 NM_197948 /// 
               
               
                   
                   
                 NM_197949 /// 
               
               
                   
                   
                 NM_197950 /// 
               
               
                   
                   
                 NM_197954 
               
               
                 223280_x_at 
                 MS4A6A 
                 NM_022349 /// 
                 chr11q12.1 
               
               
                   
                   
                 NM_152851 /// 
               
               
                   
                   
                 NM_152852 
               
               
                 223343_at 
                 MS4A7 
                 NM_021201 /// 
                 chr11q12 
               
               
                   
                   
                 NM_206938 /// 
               
               
                   
                   
                 NM_206939 /// 
               
               
                   
                   
                 NM_206940 
               
               
                 223620_at 
                 GPR34 
                 NM_001097579 
                 chrXp11.4-p11.3 
               
               
                   
                   
                 /// NM_005300 
               
               
                 223660_at 
                 ADORA3 
                 NM_000677 /// 
                 chr1p13.2 
               
               
                   
                   
                 NM_001081976 
               
               
                   
                   
                 /// NM_020683 
               
               
                 224356_x_at 
                 MS4A6A 
                 NM_022349 /// 
                 chr11q12.1 
               
               
                   
                   
                 NM_152851 /// 
               
               
                   
                   
                 NM_152852 
               
               
                 225353_s_at 
                 C1QC 
                 NM_001114101 
                 chr1p36.11 
                 M2 Marker 
                 
                   27 
                 
               
               
                   
                   
                 /// NM_172369 
               
               
                 225502_at 
                 DOCK8 
                 NM_203447 
                 chr9p24.3 
               
               
                 225646_at 
                 CTSC 
                 NM_001114173 
                 chr11q14.1-q14.3 
                 M2 Marker 
                 
                   26 
                 
               
               
                   
                   
                 /// NM_001814 /// 
               
               
                   
                   
                 NM_148170 
               
               
                 225647_s_at 
                 CTSC 
                 NM_001114173 
                 chr11q14.1-q14.3 
                 M2 Marker 
                 
                   26 
                 
               
               
                   
                   
                 /// NM_001814 /// 
               
               
                   
                   
                 NM_148170 
               
               
                 226068_at 
                 SYK 
                 NM_003177 
                 chr9q22 
               
               
                 227265_at 
                 FGL2 
                 NM_006682 
                 chr7q11.23 
               
               
                 227266_s_at 
                 FYB 
                 NM_001465 /// 
                 chr5p13.1 
               
               
                   
                   
                 NM_199335 
               
               
                 227346_at 
                 ZNFN1A1 
                 NM_006060 
                 chr7p13-p11.1 
               
               
                 227889_at 
                 AYTL1 
                 NM_017839 
                 chr16q12.2 
               
               
                 228532_at 
                 C1orf162 
                 NM_174896 
                 chr1p13.2 
               
               
                 229074_at 
                 — 
                 — 
                 — 
               
               
                 229560_at 
                 TLR8 
                 NM_138636 
                 chrXp22 
                 Innate immunity 
               
               
                 229723_at 
                 TAGAP 
                 NM_054114 /// 
                 chr6q25.3 
               
               
                   
                   
                 NM_138810 /// 
               
               
                   
                   
                 NM_152133 
               
               
                 229937_x_at 
                 LILRB1 
                 NM_001081637 
                 chr19q13.4 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001081638 
               
               
                   
                   
                 /// 
               
               
                   
                   
                 NM_001081639 
               
               
                   
                   
                 /// NM_006669 
               
               
                 230252_at 
                 GPR92 
                 NM_020400 
                 chr12p13.31 
               
               
                 230391_at 
                 — 
                 — 
                 — 
               
               
                 230550_at 
                 MS4A6A 
                 NM_022349 /// 
                 chr11q12.1 
               
               
                   
                   
                 NM_152851 /// 
               
               
                   
                   
                 NM_152852 
               
               
                 230925_at 
                 APBB1IP 
                 NM_019043 
                 chr10p12.1 
               
               
                 232617_at 
                 CTSS 
                 NM_004079 
                 chr1q21 
                 M2 Marker 
                 
                   26 
                 
               
               
                 232843_s_at 
                 DOCK8 
                 NM_203447 
                 chr9p24.3 
               
               
                 234987_at 
                 C20orf118 
                 — 
                 chr20q11.23 
               
               
                 236028_at 
                 IBSP 
                 NM_004967 
                 chr4q21-q25 
               
               
                 244434_at 
                 — 
                 — 
                 — 
               
               
                 38487_at 
                 STAB1 
                 NM_015136 
                 chr3p21.1 
                 M2 Marker 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Gene Cluster G25 
               
            
           
           
               
               
               
               
            
               
                   
                 Gene 
                   
                 Chromosomal 
               
               
                 ProbeId 
                 Symbol 
                 RefSeq.Transcript.ID 
                 Location 
               
               
                   
               
               
                   
                   
                 NM_005228 /// NM_201282 /// 
                   
               
               
                 201983_s_at 
                 EGFR 
                 NM_201283 /// NM_201284 
                 chr7p12 
               
               
                   
                   
                 NM_005228 /// NM_201282 /// 
                   
               
               
                 201984_s_at 
                 EGFR 
                 NM_201283 /// NM_201284 
                 chr7p12 
               
               
                 203373_at 
                 SOCS2 
                 NM_003877 
                 chr12q 
               
               
                 203484_at 
                 SEC61G 
                 NM_001012456 /// NM_014302 
                 chr7p11.2 
               
               
                   
                   
                 NM_005244 /// NM_172110 /// 
                   
               
               
                   
                   
                 NM_172111 /// NM_172112 /// 
                   
               
               
                 209692_at 
                 EYA2 
                 NM_172113 
                 chr20q13.1 
               
               
                 210135_s_at 
                 SHOX2 
                 NM_003030 /// NM_006884 
                 chr3q25-q26.1 
               
               
                 224999_at 
                 EGFR 
                 — 
                 chr7p12 
               
               
                 228307_at 
                 EMILIN3 
                 NM_052846 
                 chr20q11.2-q12 
               
               
                 232120_at 
                 EGFR 
                 — 
                 chr7p12 
               
               
                   
                   
                 NM_001031849 /// NM_001879 ///  
                   
               
               
                 232224_at 
                 MASP1 
                 NM_139125 
                 chr3q27-q28 
               
               
                 232539_at 
                 — 
                 — 
                 — 
               
               
                 232541_at 
                 EGFR 
                 — 
                 chr7p12 
               
               
                 232882_at 
                 FOXO1A 
                 — 
                 chr13q14.1 
               
               
                 232925_at 
                 EGFR 
                 — 
                 chr7p12 
               
               
                 232935_at 
                 LHFP 
                 — 
                 chr13q12 
               
               
                 233025_at 
                 PDZD2 
                 NM_178140 
                 chr5p13.3 
               
               
                 233044_at 
                 EGFR 
                 — 
                 chr7p12 
               
               
                 243327_at 
                 EGFR 
                 — 
                 chr7p12 
               
               
                   
               
            
           
         
       
     
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