PATENT DOCUMENT

Abstract:
A method to determine the clinical outcome of breast tumour affecting a patient if treated with an antitumoural agent against breast tumour, the said method comprising the step of assaying a sample of a breast tumour from said patient for an expression level of selected genes, by contacting mRNA sequences from the cells of this breast tumour with a set of more than 3 nucleotide sequences related to human mutated PIK3CA.

Full Description:
[0001]    This application is a Divisional application of U.S. Ser. No. 12/860,638 filed 20 Aug. 2010, which is a Continuation-in-Part Application of PCT/EP2009/052043 filed 20 Feb. 2009, which claims benefit of Ser. No. 61/030,450, filed 21 Feb. 2008 in the USA and which applications are incorporated herein by reference. To the extent appropriate, a claim of priority is made to each of the above disclosed applications. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention is related to a new detection method and a new detection kit of genes associated with PIK3CA mutation(s) and involved in PIK3/AKT pathway activation in the (luminal-B) ER-positive or HER2 positive subtypes with clinical implications. The present detection method and kit have a predictive clinical outcome (survival outcome) and could be therefore used for identifying if a patient from which this tumour sample is obtained could be submitted to a specific antitumoural treatment, especially to a tamoxifen or Herceptin treatment (or not). The present invention is also directed to the therapeutic application of a class of active compounds to be applied efficiently to the subtype of cancer detected by this method. 
       BACKGROUND OF THE INVENTION 
       [0003]    Breast cancer (BC) may be subdivided into subgroups depending on expression profile of several genes and/or protein. 
         [0004]    Her2 over expression in tumours results into a worse prognosis. BC patients having Her2 positive status are preferably not treated with anti oestrogens, but with anti Her2 drugs, such as Trastuzumab (Herceptin). 
         [0005]    For the BC patients whose tumours express ER receptor (ER group) but do not over express Her2, the over expression of several genes related to proliferation results into the classification into the luminal B subgroup, with a worse prognosis. These luminal B patients are preferably not treated with anti-oestrogens, but with more aggressive treatments (chemotherapy). 
         [0006]    Deregulated phosphatidylinositol 3-kinase (PI3K)-AKT signaling has been implicated in many hallmarks of carcinogenesis as the pathway influences multiple aspects of cell physiology. Many genomic alterations act on this pathway, activating its signaling activity, which contributes to tumor progression, metastases and resistance to treatment. 
         [0007]    PI3Ks are heterodimeric lipid kinases for which the p110α catalytic and regulatory p85 subunits are encoded by separate genes. In breast cancer, mutations of the PIK3CA gene, which codes for the p110α catalytic subunit, has been found in 18-40% of human cancers, which makes it one of the most common genetic changes in breast cancer beside p53 mutations and HER2 amplification. Expression of p110α mutants in human mammary epithelial cells induces multiple phenotypic alterations characteristic of breast tumor cells and in vivo studies with cells expressing PIK3CA mutants result in a more active PI3K pathway and induction of tumors. The lack of a homogeneous population makes it difficult to investigate the prognostic or predictive effect of PIK3CA mutations in breast cancer. Extensive cross-talk at multiple levels with other pathways both upstream and downstream of PI3K also makes the exact role of PIK3CA mutations in breast cancer difficult to elucidate. 
         [0008]    Mutations in the AKT1 pleckstrin homology domain (PHD) reported in breast cancer at a frequency of 8% may result in PI3K-independent membrane recruitment and activation of AKT1 and downstream signaling. The clinical relevance of this mutation is unknown. 
         [0009]    Given the complexity of PI3K signaling, it is important to have molecular markers that can predict for prognosis and therapeutic response for incorporation into future breast cancer clinical trials with compounds that act on this pathway. 
         [0010]    As the Kaplan-Meier analysis of the PIK3CA mutation versus the wild-type patients did not reveal any statistically significant differences in prognosis, mutation status alone may not be a sensitive marker of significant activation of the PI3K/AKT pathway that would affect tumor progression. Other downstream interactions of an extra oncogenic “hit” may be required. 
       Aims of the Invention 
       [0011]    A first aim of the present invention is to propose a new detection method and new detection means (kit) of improving clinical outcome (especially survival outcome) of a human patient following application of this detection method upon a tumour sample obtained from this patient and the defining (selecting among known treatments) the most effective treatment that could be applied to this patient. 
         [0012]    In particular, the present invention aims to provide such detection method and kit which allows a better discrimination of clinical outcome of patients with ER-positive and/or HER2-positive sub-types tumour samples and to identify which type of patients should receive (be prescribed) an anti oestrogen, more preferably a tamoxifen or aromatase inhibitor therapy or Herceptin related therapy or hormone/chemo, radio- or immunotherapy. 
       SUMMARY OF THE INVENTION 
       [0013]    The present invention is related to a method and a kit for a detection of mutated PIK3CA gene and/or mutated AKT-1 gene and/or gene(s) involved PIK3/AKT pathway activation(s) in (especially in high proliferative luminal-B) ER-positive [BC] or HER2-positive subtype tumour sample as described in the enclosed set of claims. 
         [0014]    The inventors have investigated frequency, phenotype and clinical relevance associated with PIK3CA or AKT-1 mutations in a large homogenous data set of ER+(BC), tamoxifen-only treated breast tumours. The inventors have examined the associated gene expression profiles to further understand the biology associated with PIK3CA or AKT-1 mutations when they activate the PI3K/AKT pathway. 
         [0015]    The inventors have selected a preferred gene set related to mutated PIK3CA and/or AKT, comprising the 81 genes of Table 2a or the 65 genes of Table 2b, more preferably the 38 genes of Table 4. 
         [0016]    The inventors have selected an alternative preferred gene set related to mutated PIK3CA and/or AKT, comprising the 278 genes of Table 5 or, more preferably, the 14 genes of Table 6. 
         [0017]    The inventors further found other (isolated) genes associated with mutated PIK3CA and/or Akt mutations, advantageously, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or all the 12 genes selected from the group consisting of the following genes: PML (Entrez gene ID 5371), PP2A (Entrez gene ID 5523, 5525, 5526), IRS2 (Entrez gene ID 8660), PIK3R1 (Entrez gene ID 5295), ESR1 (Entrez gene ID 2099), FOXO3A (Entrez gene ID 2309), P21 (PAK2) (Entrez gene ID 5062), RPS6K (Entrez gene ID 6198), EIF4E (Entrez gene ID 1977), RHEB (Entrez gene ID 6009), P27 (Entrez gene ID 1785), PI3K (Entrez gene ID 18708) and possibly their isoforms or variants. 
         [0018]    The use of the gene set(s) or of the method according to the invention allows an efficient establishment of PIK3CA mutated signature and the use of these gene sets or of the method according to the invention allows accurate and sensitive determination of the state of activation of the PI3K/AKT pathway, similar to that induced by a PIK3CA or a AKT1 mutation. 
         [0019]    The present invention is further related to a method to determine the clinical outcome (preferably the survival outcome) of a (breast) tumour affecting a patient, if this patient is treated with an anti oestrogen agent against this (breast) tumour, this method comprising the step of assaying a sample of this breast tumour obtained from this patient for an expression level of one or more gene(s) or synthesis of corresponding protein(s) encoded by these gene(s), preferably more than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 genes (including isoforms and variants) or proteins selected from the Table 2a, from mutated PIK3CA genes and proteins and/or from mutated AKT-1 genes or proteins involved in the PI3K/AKT pathway. 
         [0020]    By one or more gene(s), it is meant 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 and every number till 81 genes mentioned and identified in these tables 2a, 2b or 4, with every possible combination of selected genes (or corresponding proteins and fragments thereof). 
         [0021]    The present invention is also related to a method to determine a prognosis and/or prediction of a response of a patient having a (breast) tumour to a treatment, if treated with an anti oestrogen agent against this (breast) tumour, and comprising the step of assaying for an expression level of one or more (preferably more than 3, 9, 10, 19 or all of the gene(s) or protein(s) of (Table 2a or Table 2b or Table 4 or Table 5 or of table 6), of mutated PIK3CA/AKT-1 genes or proteins or of genes or proteins involved in the PI3K/AKT pathway activation from a breast cancer cells obtained from a breast cancer tumour sample from the patient. 
         [0022]    The method may also comprise a step of determining a clinical outcome, preferably a survival outcome correlated to an assaying step of the patient and/or a step of selecting an antitumoural compound, (especially an anti oestrogen agent), which could be administrated to this patient. 
         [0023]    In the method according to the invention, the expression levels are indicative of probabilities of recurrence (or relapsing) of cancer, possibly through metastasis. 
         [0024]    By anti oestrogen, it is meant the administration of a selective oestrogen receptor modulator (SERM), a selective oestrogen receptor down regulator (SERD), tamoxifen, raloxifene, faslodex, or a mixture thereof. 
         [0025]    In the method according to the invention, the anti oestrogen agent against breast cancer is also any compound that could be used in hormonal therapy of cancer, preferably by administration of an efficient compound selected from the group consisting of a selective oestrogen receptor modulator (SERM), a selective oestrogen receptor down regulator (SERD), preferably tamoxifen, raloxifene, faslodex or a mixture thereof, GnRH analog or a aromatase inhibitor (AI) such as Letrozole, Anastrozle or Exemestane. 
         [0026]    In the method according to the invention, the breast tumour is a HER2+ OR ER+(BC) tumour, especially a luminal-B ER+ tumour evidenced by high expression of proliferative genes. 
         [0027]    By HER2-positive, it is meant HER2 over expression. This status is measured at gene level {i.e. amplification}, at mRNA level or at the protein level and wherein this over expression in BC tumours results into a worse prognosis. 
         [0028]    BC patients having HER2 positive status are generally not treated with anti oestrogens as they are relatively resistant to their effects. 
         [0029]    By luminal B, it is meant a highly proliferative tumour (ER+ and Her2−), preferably demonstrated using published prognostic gene expression profiles such as GGI, Oncotype Dx, Intrinsic gene set, Amsterdam 70-gene signature, Rotterdam 76-gene signature, Wound-response signature or having K167 high expression (&gt;5%). 
         [0030]    Luminal B represents a worse prognosis. These luminal B patients are generally not treated with anti-oestrogens alone. 
         [0031]    In the method of the invention, the step of assaying for the expression level of one or more gene(s), protein(s) or portions thereof comprises a detection of target nucleic acids prepared by a mRNA amplification from the sample, by a detection of (the amplified) target nucleic acids from the sample, by a quantitative PCR, (preferably a qRT PCR), by a detection of corresponding target proteins or their fragments through specific binding with corresponding capture antibodies or similar capture molecules (nanobodies, specific Hypervariable portions of antibodies, etc), preferably such detection of target proteins is obtained in patient blood or in breast cancer epithelial cells enriched from patient blood. 
         [0032]    Advantageously, in the method according to the invention, the detected target genes or proteins are selected from the group consisting of more than 3 genes (9, or 15) or corresponding proteins of the genes presented in Table 2a, Table 2b or Table 4 (or Table 5 or 6) or genes involved in PI3K/AKT pathway activation. 
         [0033]    Advantageously, at least one gene selected from the group comprising PFN2, ORC5L, MYC, E2F5, ARPP19 and MNAT1 (the first group of these genes being under expressed in PIK3CA mutated subjects) and at least one gene selected from the group comprising SCGB2A2, NOTCH2, TNIK, GOLPH2, ARHGDIB, GALNT2, SPTLC2 and SCGDAD2 (these genes of the second group being over expressed in PIK3CA mutated subjects), wherein at least three gene are selected. 
         [0034]    In the method according to the invention, the sample could be obtained by various techniques, preferably by biopsy, more preferably by a minimally invasive technique or selected from core biopsy, excisional biopsy, ductal lavage simple, a fine needle aspiration sample or from cells micro dissected from the sample. 
         [0035]    Another aspect of the present invention is related to a set of capture nucleotide sequences comprising one or more strand(s) of sufficient length of about 15 to about 250 or more nucleotides for obtaining an efficient and specific hybridization of corresponding target nucleotide sequences (RNA sequences) of human mutated PIK3CA/AKT-1 sequences or sequences involved in PI3K/AKT pathway activation, especially one or more sequence(s) of Table 2a, Table 2b or Table 4 or capture molecules (antibodies, etc) that may bind specifically these corresponding target proteins, wherein at least a portion of this set is hybridized to nucleotides quantitatively amplified from RNA sequences of breast cells. 
         [0036]    Advantageously, the set of capture nucleotide sequences or capture molecules that may bind the proteins is immobilised on a solid support surface as a microarray. 
         [0037]    Preferably, (specific) hybridisation between capture and target sequences is obtained under stringent conditions (under conditions well-known to the person skilled in the art, for instance, the one described by S AMBROOK ET AL ) which provides sufficient binding efficiency of the target sequences on their specific capture probes to the detected with no or very low, preferably lower than 5% and even lower than 1%, cross-hybridization on non-related target capture probes. 
         [0038]    Advantageously, the hybridized target nucleotide sequences are previously amplified from RNA sequences of breast cells. 
         [0039]    Advantageously, the breast tumour cell is ER+ (BC) or HER2+ tumour cells. 
         [0040]    A further aspect of the present invention is related to this set, wherein the mutated genes comprise mutation(s) in the PIK3CA mutated sequences are PIK3CA mutations selected from a group consisting of A3140G, A3150T in EXON20 of the genomic DNA and/or G1633A, G1624A or G1634A in EXONS of the genomic DNA and corresponding nucleotide of messenger RNA sequence. 
         [0041]    More preferably, the set according to the invention comprises more than 3, 5, 10, 15 or all the sequences selected from the group consisting of the sequences above-described and present in a Table 2a, Table 2b or Table 4 or present in Tables 5 or 6. 
         [0042]    Advantageously, the set according to the invention may also further comprise one or more genes selected from the group consisting of IL17BR (55540), CHDH (55349), QPRT (23475), HOXB13 (10481) genes wherein over expression of IL17BR and/or CHDH sequences and/or under expression of QPRT and/or HOXN13 sequences are negative prognosis of selective oestrogen receptor modulator SERM treatment of oestrogen receptor positive patient. 
         [0043]    Another aspect of the invention is identifying a subgroup of Her2 positive breast cancer (patients) having the signature of mutated PIK3CA (preferably identified by the method of the invention), that would benefit from anti oestrogen treatment 
         [0044]    Another aspect of the invention is therefore anti oestrogen for use in the treatment of Her2 positive breast cancer (patients) having the signature of mutated PIK3CA and being preferably identified by the method of the invention. 
         [0045]    Another aspect of the invention is anti oestrogen for use in the treatment of ER positive, luminal B breast cancer (patients) having the signature of mutated PIK3CA. 
         [0046]    The method and kit according to the invention could be also combined with one or more detection method, kit and tools already described in the state of the art especially in the document WO 2006/119593, especially prognostic means (signature) or gene list (gene set) which could be used for an efficient prognosis (prognostic) of cancer in ER+ patient, but also possibly in ER− patient such as the one described by W ANG ET AL . (2005), L ANCET  365, page 671-679, V AN &#39;T V EER ET AL . (2002), Nature 415, pages 530-536, PAIK  ET AL . (2004) New ENGL. J. MED. 351, pages 2817-2826, TESCHENDORF  ET AL . (2006). Genome Biol. 7, R101 206, VAN DE VIJVER  ET AL . (2002) New ENGL. J. MED. 347, pages 1999-2009, PEROU  ET AL . (2000) Nature, 406, pages 747-752, SOTIRIOU  ET AL  (2003) PNAS 100, pages 10393-10398, S ORLIE ET AL . (2001) PNAS 98, pages 10869-10874, M ILLER ET AL . (2005) PNAS 102, pages 13550-13555, N ADERI ET AL . (2007) Oncogene 26, pages 1507-1516, P AIK ET AL . (2006) J. Clin. Oncol. 24, pages 3726-3734, S OTIRIOU ET AL . (2006) J. Natl. Cancer Inst., 98, pages 262-272, C HANG ET AL . (2004) PLOS BIOL 2: E7, S ORLIE ET AL . (2003) PNAS 100, pages 8418-8423, I VSHINA ET AL . (2006) Cancer Res. 66, pages 10292-10301, P AWITAN ET AL ., (2005) Breast Cancer Res; 7: R953-964, F ARMER ET AL . (2005) Oncogene 24, pages 4660-4671, W HITFIELD ET AL . (2006) Nat. Rev. Cancer 6, pages 99-106, and the expression profiling protein used in breast cancer as described in document WO2005/071419, the expression profiling protein/gene described in the document WO2005/021788. The set of the invention may also comprise or consist of capture nucleotide sequences or capture molecules that can bind specifically the proteins encoded by these genes of these nucleotide or proteins sets. 
         [0047]    Another aspect of the present invention is related to a kit or device, preferably a computerised system comprising a bioassay module configured for detecting gene expression (or protein synthesis) from a tumour sample which is based upon the genes set including molecules that bind specifically the proteins encoded by these genes set according to the invention and a processor module configured to calculate expression (over or under expression) of these genes and/or synthesis of corresponding encoded proteins and to generate a clinical outcome, preferably a survival outcome and a risk assessment for a tumour sample (risk assessment to develop a malignant tumour) or susceptibility that a patient from which this tumour sample has been obtained could be treated by efficient therapeutic treatment, especially a treatment based upon the administration of an anti oestrogen, preferably tamoxifen. Advantageously, the generated set of genes (and proteins) according to the invention may also provide a detection of tumour correlated with a Herceptin (Trastuzumab Genentech, California USA) resistance in HER2 tumour samples. Therefore, the method of the invention could be used in patients presenting a HER2 subtype combined with this resistance for selecting an appropriate treatment that is not based upon administration of Herceptin to the patient 
         [0048]    The inventors have measured that the signature of the invention (mutated signature of PIK3CA and/or Akt) predicts for a better outcome of anti-oestrogen treatments of BC patients. 
         [0049]    The inventors have measured that the signature of the invention (mutated signature of PIK3CA and/or Akt) predicts for a better outcome of anti-oestrogen treatments in luminal B BC patients. 
         [0050]    The inventors have measured that luminal B BC patients having the mutated PIK3CA and/or Akt signature according to the invention benefit from anti-oestrogen treatments. 
         [0051]    Surprisingly, the inventors have observed that the mutated signature of PIK3CA and/or Akt in ER+ and HER2+ BC patients predicts for a better outcome. 
         [0052]    Surprisingly, the inventors have observed that the mutated signature of PIK3CA and/or Akt in ER+(including for luminal B patients) and HER2 positive BC patients predicts for a better response to anti oestrogens, possibly in addition for Her2 positive BC patients of anti HER2 drugs, such as Herceptin (trastuzumab). 
         [0053]    The inventors have therefore treated with anti oestrogen BC patients with the PIK3CA mutated signature identified according to the method of the invention. 
         [0054]    The BC patients (with the PIK3CA mutated signature) treated (according to the invention) with anti oestrogen are preferably ER positive. 
         [0055]    The BC patients (with the PIK3CA mutated signature) treated (according to the invention) with anti oestrogen are luminal B ER positive. 
         [0056]    The BC (with the PIK3CA mutated signature) treated (according to the invention) with anti oestrogen are Her2 positive. 
         [0057]    Conversely, the inventors have observed that chemotherapy is less effective in BC patients having the gene signature of mutated PIK3CA and/or Akt, according to the present invention. 
         [0058]    The inventors have further observed that radiotherapy is less effective in BC patients having the gene signature of mutated PIK3CA and/or Akt, according to the present invention. 
         [0059]    The inventors have further observed that PI3kinase/AKT/mTOR pathway inhibitors are less effective in BC patients having the gene signature of mutated PIK3CA and/or Akt, according to the present invention. 
         [0060]    The method, gene(protein) set and kit (or tools) according to the invention could be also used for selecting an adequate therapeutic treatment to get apply to the patient from which the tumour sample has been obtained, especially selecting an appropriate dose and/or schedule of chemo-therapeutic and/or bio-pharmaceutical and/or targeted agent. 
         [0000]    This treatment could be based upon administration of anti oestrogens, taxanes, anthracyclines, CHOP or other drugs like velcade, fluorouracil, uracil, vinblastine, gemcitabine, methotrexate, goserelin, irinotecan, thiotepa, topotecan, toremifene, anti-EGFR, anti-HER2/neu, anti-VEGF, RTK-inhibitor, anti-VEGFR, GRH, anti-EGFR/VEGF, HER2/neu, EGF-R or anti-HER2. 
         [0061]    The method, set and kit according to the invention could be also used in combination with a method for controlling the efficiency of the treated method or an active compound in cancer therapy. Indeed, the method, set and kit (or tools) according to the invention that apply for an efficient prognostic of cancer in various breast cancer types could also be used for an efficient monitoring of the treatment applying to the patient suffering from this cancer. 
         [0062]    The method according to the invention may require a first prognostic step which is applied to the patient before submitting the patient to a treatment or to a second diagnosis step following this treatment. 
         [0063]    This method could be applied several times (two time, three times, four times, five times, etc) to the mammal subject (human patient) during the treatment or during the monitoring of the treatment several weeks (one week, two weeks, three weeks, four weeks, etc) or months (one month, two months, three months, etc) after the end of the treatment to reveal if a modification of gene expression or protein synthesis in a sample subject is obtained following the treatment. 
     
    
     
       DETAILED DESCRIPTION OF THE INVENTION 
       Figure Legends 
         [0064]      FIG. 1  shows that there was no correlation between PIK3CA mutations and the luminal subtypes defined using the GG values, evidencing that PIK3CA mutations are not associated with either molecular ER-positive subtypes. In contrast, the inventors did surprisingly find an association between the expression levels of the associated PI3K mutation signature and the molecular subtypes. Indeed, higher levels of PI3K associated mutation signature were associated with the HER2 and luminal A low proliferate subtypes. 
           [0065]      FIG. 2  presents a Kaplan-Meier analysis revealed that PIK3CA mutations were surprisingly not significantly associated with a better or worse prognosis compared with those tumours without a mutation. Analyses of exon 9 and 20 mutations separately did not change this result. Univariate survival analysis confirmed no significant correlation between PIK3CA mutations and prognosis. 
           [0066]      FIG. 3  shows surprisingly that higher expression levels of the PIK3CA signature were associated with statistically better clinical outcome when tamoxifen only treated patient were considered. 
           [0067]      FIG. 4  shows the association between the expression levels of the PIK3CA signature and clinical outcome was better evidenced within the highly proliferative high risk luminal B tumours. Tumours with higher expression levels of the signature benefit better from tamoxifen than those with lower expression levels. 
           [0068]      FIG. 5  presents results that are similar in the breast cancer patients who had received no systemic treatment and that the group of patients with higher expression levels of the PIK3CA mutation signature had better clinical outcome than those with lower expression levels as shown by this KM curve analysis. 
           [0069]      FIG. 6  shows the association between the expression levels of the PIK3CA signature and clinical outcome was only seen within the highly proliferative high risk luminal B tumours. Surprisingly, tumours with higher expression levels of the signature showed better clinical outcome than with lower expression levels. 
       
    
    
     MATERIALS AND METHODS 
     Tumour Samples Screened for Mutation Status 
       [0070]    Primary breast cancer tumour samples from a previously described “tamoxifen-only treated” data set (Loi, 2007; J. Clin Oncol., 25, 1239-46;) were collected for DNA extraction and mutation analysis. The inventors obtained DNA from 173 samples for PIK3CA mutation sequencing and from 131 samples for AKT1 mutation analysis. The median follow-up of these samples was 9.0 yrs (range: 8.2-9.8 yrs), with 45 (28%) distant metastatic events. 
       Screening for Mutations 
     PIK3CA 
       [0071]    The vast majority (&gt;85%) of PIK3CA mutations reported in human breast cancers are missense mutations clustering in exons 9 (E545K) and 20 (H1047R). (S AAL , 2005) These exons we screened for mutations using single strand conformation polymorphism (SSCP). The PIK3CA primer sets are as follows: 
         [0000]                              Exon 9:            Forward: {6FAM}TGAAAATGTATTTGCTTTTTCTGT;   SEQ ID N° 3               Reverse: {VIC}TGTAAATTCTGCTTTATTTATTCC;   SEQ ID N° 4               Exon 20:           Forward: {NED}TCCAAACTGACCAAACTGTTCTT;   SEQ ID N° 5               Reverse: {PE}TCCAGAGTGAGCTTTCATTTTCTC.   SEQ ID N° 6            
Primers labeled with 5′ fluorescence (Applied Biosystems). PCR was carried out with 10 ng of genomic DNA in a reaction volume of 10 μL, with the inclusion of 0.25 units Hot Star TaqDNA polymerase (Q IAGEN , Valencia, Calif.). After an initial denaturation step of 95° C. for 10 minutes, a “touch-down” program was used consisting of 2 cycles of amplification at annealing temperatures of 63° C. to 59° C.; followed by 30 amplification cycles at an annealing temperature of 58° C. and a final extension cycle of 72° C. for 5 minutes. Samples were prepared for single-strand conformational polymorphism (SSCP) analysis using the ABI-3130 automated capillary sequencer. The sample, size standard and Hi-Di™ Formamide was mixed in each well of sample plate. The PCR-product was denatured for 3 minutes at 95° C. and then cooled on ice for minutes to avoid re-annealing of the complementary strands before being run using the Genemapper fragment analysis module on ABI 3130 genetic analyzer. Labelled fragments are visualized on an Applied Biosystems DNA analyzer. The genescan LIZ® size standard was used in all samples as an internal ladder to align data from different capillaries and eliminate capillary-to-capillary or run-to-run variability. Cases showing aberrant peak shifts by SSCP were reamplified and sequenced directly with the BigDye terminator method (Applied Biosystems; Warrington, United Kingdom or Forster City, Calif.) on an auto sequencer (ABI PRISM 3100).
 
       AKT1 
       [0072]    The mutation screening for AKT1 exon 4 was carried by High-Resolution Melting (HRM) analysis. These exons were screened for mutations using capillary electrophoresis single strand conformation polymorphism (CESSCP) 
         [0000]    The AKT1 primer sets are as follows: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                 Exon 4 
               
             
          
           
               
                   
                 Forward: AGGGTCTGACCCCTAGAGATG 
                 SEQ ID N° 1 
               
               
                   
               
               
                   
                 Reverse: AGAGGGCTCCAGCCAACC 
                 SEQ ID N° 2 
               
             
          
         
       
     
         [0073]    PCR was carried out with 15 ng of genomic DNA in a reaction volume of 10 μL, including 5 μL of the High-Resolution Melting Master (Roche) for amplification and detection of heteroduplex regions in PCR amplicons. The High-resolution melting master contains a dye, ResoLight that enables detection of double-stranded DNA by fluorescence, monitoring formation of amplicons during PCR cycling, and melt curve analysis. Samples were carried out in duplicate, in a 96-well plate. After an initial denaturation step of 95° C. for 15 minutes, a touch-down program was used consisting of 2 cycles of amplification at annealing temperatures of 63° C. to 59° C.; followed by 55 amplification cycles at an annealing temperature of 58° C. and a final Melt from 70° C. to 95° C. PCR cycling and HRM analysis was performed on the Light Cycler 480 (Roche Diagnostics; F. Hoffmann-La Roche Ltd.). LightCycler480 Software (v1.3.0.0705) was used to analyse results. Samples with variations in DNA sequence are distinguished by discrepancies in melting curve shape. Samples showing deviations in melt curve were treated with ExoSapIT (GE Healthcare, Buckinghamshire, England) according to the manufacturer&#39;s instructions and sequenced directly with the BigDye terminator method (Applied Biosystems; Warrington, United Kingdom or Forster City, Calif.) on an auto sequencer (ABI PRISM 3100). 
       Microarray Analysis 
       [0074]    Part of the tamoxifen-treated dataset has previously been described (Loi, 2007). Another 77 primary breast cancer samples also treated with tamoxifen monotherapy with corresponding Affymetrix gene expression data was also used for the survival analysis. 
         [0075]    For the survival analysis using breast cancer samples which had received no systemic treatment (hereby referred to as the “untreated” dataset), gene expression data was used from datasets described in D ESMEDT ET AL ., 2007, Clin Cancer Res., 13, 3207-14; W ANG ET AL.,  2005 and  VAN DE VIJVER ET AL.,  2002. 
         [0076]    The inventors used the normalized data (log 2 intensity in single-channel platforms or log 2 ratio in dual-channel platforms) as published by the original studies. Hybridization probes were mapped to Entrez GeneID. When multiple probes were mapped to the same GeneID, the one with the highest variance in a particular dataset was selected to represent the GeneID. 
         [0077]    Data analyses between performed using BRB ArrayTools version 3.5 developed by Dr. Richard Simon and Amy Peng Lam (http://linus.nci.nih.gov/BRB-ArrayTools.html). Differential gene expression between PIK3CA mutation carriers versus non-mutation carriers was performed using the “class comparison” tool. A two sample t-test was used at a significance value of 0.001 and statistical significance of the gene expression profiles between the classes was tested by 1000 permutations of the class labels. For this analysis, of the 173 sequenced for PIK3CA mutations, 161 had corresponding microarray data. Only those samples with exon 20 mutations were used in the class comparison analysis. 
         [0078]    The inventors have developed an index called the PIK3CA index that could measure the similarity between the expression profile of any given tumour sample and the PI3K/AKT pathway activation by breast cancers with a PIK3CA mutation. The signature score is the sum of the expression of the genes up-regulated in the mutated tumours minus the sum of the expression of the genes up-regulated in the wild type tumours. 
       PIK3CA Index: 
       [0079]    
       
         
           
             
               
                 ∑ 
                 
                   i 
                   ∈ 
                   P 
                 
                 
                     
                 
               
                
               
                   
               
                
               
                 x 
                 i 
               
             
             - 
             
               
                 ∑ 
                 
                   j 
                   ∈ 
                   N 
                 
                 
                     
                 
               
                
               
                   
               
                
               
                 x 
                 j 
               
             
           
         
       
     
         [0000]    where P is the set of genes up-regulated in the mutated tumours and N is the set of genes up-regulated in the wild type tumours. 
         [0080]    The weight of the genes was either +1 or −1 depending on their association with PIK3CA mutation status. As a result, the index was not optimized to specifically identify mutation positive samples. Advantageously, no clinical outcome data was used to identify the genes used in the PIK3CA index hence the inventors were able to use the tamoxifen-treated dataset for the survival analyses. 
       Interaction Networks and Functional Analysis 
       [0081]    Gene oncology and gene interaction analyses were carried out using Ingenuity Pathways Analysis (IPA) version 3.0 (http://www.ingenuity.com). The gene lists containing the Affymetrix probe, as well as the fold change was inputted into IPA and mapped to the corresponding gene object in the database. These focus genes were then used to generate the networks based on the curated list of molecular interactions in the IPA database. Significance of enrichment is determined by a right-tailed Fisher&#39;s exact test, using a list of all the genes on the array as a reference set. 
       Statistical Analysis 
       [0082]    Statistical analysis was performed using the SPSS statistical software package (SPSS Inc. Chicago, Ill.) version 13.0. The chi-square test was used to evaluate for possible associations between mutation status and the various clinico-pathological factors. In the univariate and multivariate Cox regression, the histologic grade (grade 1 and. 2 vs. 3), tumour size (≦2 cm vs. &gt;2 cm), nodal status (positive vs. negative) and age (≦50 vs. &gt;50 yrs) were treated as binary variables. The PIK3CA gene signature was treated as a continuous variable. Survival outcomes were also estimated with the Kaplan-Meier method and compared using the log-rank statistic. The PIK3CA gene signature was dichotomized to form two groups for the illustration by Kaplan-Meier survival curves using a cut-off at 66:33% as survival of PIK3CA-GS highest two tertiles of dataset were similar. The group with the higher and lower expression of the PIK3CA-GS is referred to as “mt-like” and “wt-like” respectively. 
         [0083]    Breast cancer molecular subgroups were defined using a previously reported method of W IRAPATI ET AL,  2008, Breast cancer cell, 10, R65. The gene expression grade index (GGI) was used as a quantification of the expression of proliferation genes (S OTIRIOU ET AL , 2006). For ER+ BC subtypes, proliferation expression was used to classify tumours representing the luminal-A and-B molecular subgroups described by P EROU ET AL ., 2000, into luminal low-risk and luminal high-risk subgroups respectively (L OI,  2007). 
       Results 
     Frequency and Location of Mutations 
       [0084]    Mutational analysis of the PIK3CA gene was performed in 173 primary ER+BCs. A total of 46 mutations were found (26%). The majority (71%) of these mutations were located on exon 20. One sample had mutations in both exon 9 and 20. Twenty-nine (91%) of mutations on exon 20 were H1047R substitutions, its high frequency consistent with previous reports (Table 1). Five AKT1 mutations were found in the 131 samples that were able to be tested (3.8%). All 5 mutations were E17K substitutions, were found in PIK3CA wild type samples. 
         [0000]    Mutations and Correlation with Clinico-Pathological Features 
         [0085]    There were no significant correlations between PIK3CA mutations and other important clinico-pathologic features, except a borderline association with tumour size (p=0.057) (Table 1). Similarly, AKT1 mutations were not associated with any clinical factors, though the small numbers make this result difficult to interpret. Kaplan-Meier analysis revealed that mutations of PIK3CA ( FIG. 2 ), AKT1 or both were not significantly correlated with prognosis compared with those tumours without a mutation. PIK3CA exon 9 and 20 mutations were examined combined and separately and results were similar. Univariate survival analysis confirmed no significant correlation between both mutations and prognosis. There was no correlation between either mutation and gene expression grade (GGI) values, suggesting that these mutations are not associated with a particular ER+ molecular subtype. There was no significant association with PIK3CA mutation and ERBB2 or PTEN over expression (p=0.4 and 0.1 respectively). 
       Microarray Analysis 
       [0086]    The lack of correlation of PIK3CA mutations with prognosis with other studies may be due to the unique features of this patient dataset (all ER+ tumours), or that PIK3CA mutations may predict favourably for tamoxifen treatment. Another possibility is that PIK3CA mutations alone are not prognostic in breast cancer but may need to interact with other genetic changes in cancer cells to affect prognosis or other properties of the cancer cells. The corresponding gene expression data was therefore examined with the aim to gain further insight into the biology of activation of the PI3K/AKT pathway through PIK3CA mutations in ER+ BC. 
       PIK3CA Mutation-Positive Associated Differential Gene Expression Signature and Interaction Networks 
       [0087]    Firstly, those breast cancers harboring PIK3CA exon 20 mutations with available transcriptional profiles (n=28) were compared to wild type samples (n=120). Using a supervised analysis, 81 probe sets were found to be significantly differentially expressed at the nominated t-test level (see Table 2a or the refined tables 2b and Table 4; the genes of Tables 2b and of table 4 are the most suitable genes selected from the Table 2a). The statistical significance of the class label permutation was significant at a p value of 0.03, confirming that the gene expression profiles were significantly different between classes. Results were similar if all mutation samples (exon 9 and 20) were used. 
         [0088]    The inventors then performed another statistical analysis by combining the extent of up- or down-regulation (&gt;1.3) and the statistical significance (p&lt;0.05) of a selected gene in mutated cells (Table 5) and further deduce a most preferred signature (Table 6 representing the genes present in both Tables 4 and 5). 
         [0089]    The molecular interactions of these differentially expressed genes were examined using Ingenuity Pathways Analysis (IPA). According to Ingenuity Pathways Analysis (IPA), the top canonical pathway was insulin receptor signalling (p=0.002) and the top function was protein synthesis (p=0.0005) 
         [0000]    Overall, these data were consistent with the notion that the PI3K pathway is activated by PIK3CA mutations and PIK3CA mutations in breast cancer are associated with a distinct molecular profile.
 
Activation of the PI3K/AKT Pathway Due to PIK3CA Mutations Predicts Outcome of ER+BC Treated with Adjuvant Tamoxifen.
 
         [0090]    As the molecular profile of the breast cancer samples with a PIK3CA mutation seemed to represent activation of the PI3K/AKT pathway, the inventors went on to create an index using the differentially expressed genes that would be able to quantify the extent of activation of the pathway in a given tumour sample. In this way, the inventors were able to encapsulate clinically relevant activation of this pathway through other mechanisms as well as PIK3CA mutations. 
         [0091]    The inventors further found the gene signature of the differentially expressed genes corresponding to mutated PIK3CA and/or AKT in (PIK3CA and/or AKT) wt patients and conclude that the mutated signature they evidenced represents a more physiological read out than the qualitative identification of a mutation in PIK3CA and/or AKT gene(s). 
         [0092]    Firstly, the inventors looked at correlation between the PIK3CA mutated signature and subtypes of cancers. 
         [0093]    The inventors found no correlation with luminal status of ER+ Breast cancers ( FIG. 1 ). 
         [0094]    The inventors found a positive correlation between Her2 positive status and PIK3CA mutated signature ( FIG. 1 ). 
         [0095]    The inventors looked at prognostic ability of PIK3CA index in the dataset of ER+, (HER2-negative) tamoxifen-treated patients. Surprisingly, an increasing expression level of index was associated with a significantly better outcome in these patients (log rank p value: 0.004— FIG. 3 ). These results were similar in the 405 available patient samples which had not received any systemic treatment (p value: 0.04— FIG. 5 ). The inventors then went on to look at the relevance of PI3K/AKT activation in the 2 molecular subtypes of ER+ BC. Interestingly, in the tamoxifen-treated group, the PIK3CA index was able to separate the luminal-B, but not the luminal-A group of breast cancers into two prognostically distinct groups (p=0.02;  FIG. 6 ). This phenomenon was also observed in the untreated dataset ( FIG. 4 ). However, it noteworthy that in the tamoxifen dataset, the outcome of the luminal-B group treated with tamoxifen with high expression of the PIK3CA index ( FIG. 6 ) seemed to nearly approximate the survival curves of the luminal-A tumours for the first 5 years, suggesting that tamoxifen may, in fact, have a beneficial effect on outcome in this subgroup. Overall, these data suggest that the high expression of the PIK3CA mutation index and hence increased activation of the PI3K/AKT pathway through PIK3CA mutations may predict favourably for tamoxifen treatment in the luminal-B, highly proliferative ER+ BCs. 
         [0096]    Univariate and multivariate analyses confirmed that the PIK3CA index was able to provide independent prognostic information the tamoxifen dataset (Table 3) 
         [0097]    The inventors further looked at the response of Her2 positive BC patients treated with tamoxifen and observed that the Her2 positive BC patients having the mutated PIK3CA signature responded better to tamoxifen than the other Her2 positive patients. 
         [0098]    The inventors conclude that anti oestrogen treatments may be useful for Her2 positive BC patients having the mutated PIK3CA signature. 
         [0099]    The overall incidence of PIK3CA mutations found in this current study is within the range of the four other reported large studies on PIK3CA mutations in breast cancer, even though the analysis of the PIK3CA gene in this study was restricted to exons 9 and 20 only. In contrast to other studies, the majority of mutations found were located on exon 20. This is most likely, because almost all of the breast cancers in this data set were invasive ductal carcinomas, consistent with previous observations that exon 9 mutations are more common in invasive lobular carcinoma. The incidence of PIK3CA mutations observed to date makes it one of the commonest genetic alterations in breast cancer. 
         [0100]    This study, similar to others, did not find a particular association of PIK3CA mutations with breast cancer clinico-pathological characteristics (Table 1). The only consistent finding thus far has been the association between PIK3CA mutations and a positive ER status. 
         [0101]    The inventors report here for the first time the incidence and clinical outcome of AKT1 PHD mutations in ER+ BC treated with adjuvant tamoxifen monotherapy. AKT1 PHD mutations have been reported to activate the PI3K/AKT pathway. The incidence here was lower than previously reported (3.8% vs. 8%), which makes the results from further analyses difficult to interpret. Interestingly, all AKT1 mutations occurred in PIK3CA wild type samples. However, neither PIK3CA and/or AKT1 PHD mutations per se were associated with prognosis in our ER+ BC dataset. These data does not support a recent study which reported that in breast cancer, PIK3CA mutations located on exon 9 conveyed a worse prognosis that those located on exon 20, though the incidence of exon 9 mutations here was less. Given the conflicting data in the literature and the low incidence of AKT1 mutations, it seems it may be impossible to use PIK3CA and AKT1 mutation status alone to predict prognosis and treatment response. AKT1 PHD mutations may even predict for a favourable prognosis given that cell line and animal models suggest that unlike AKT2, AKT1 does not influence invasion and metastases. 
         [0102]    However, the PI3K/AKT pathway is complex, impacting on multiple areas of cell physiology, hence activation of the pathway by different mechanisms is likely to trigger different cellular functions. Using the corresponding gene expression data, the inventors were able to identify a molecular profile from PIK3CA mutation positive breast cancers. The inventors then used the 81 genes to form an index that could quantify the level of PI3K/AKT pathway activation of a given tumour similar to that triggered by a PIK3CA mutation. Interestingly, the inventors found that in ER+ BC, high expression of the index, or activation of the PI3K/AKT pathway seemed to predict for a better outcome and also a beneficial effect from tamoxifen treatment. This finding was most impressive in the luminal-B subgroup, which normally has a poor prognosis compared with the luminal-A subgroup. The index was relevant to tumour samples that were negative for PIK3CA mutations, implying that those tumours with high expression of the PIK3CA signature had clinically relevant PI3K/AKT pathway deregulation through some other mechanism. The PIK3CA signature could therefore be a better indicator of pathway dysfunction than mutation status per se. 
         [0103]    Given the multiple levels of molecular interactions in the PI3K/AKT pathway, it is not inconceivable that different activators of the pathway will be associated with different transcriptional profiles and clinical outcomes. 
         [0104]    In cell lines, PIK3CA mutant lines including MCF7 and T47D, were found to be more sensitive to tamoxifen than PIK3CA normal lines. These results may be extremely significant for the luminal-B subtype as it could identify which tumours may benefit from endocrine therapy and which tumours will require other treatments to alter its poor prognosis. It will also be important in the future to determine whether the PIK3CA gene set can predict response to PI3K inhibitors. 
         [0105]    The inventors report that PIK3CA mutations and for the first time, AKT1 mutations do not correlate with prognosis in a large cohort of ER+ BCs treated with adjuvant tamoxifen monotherapy. The inventors disclose a gene signature that identifies those ER+ BCs with clinically relevant activation of the PI3K/AKT pathway, and identify those breast cancers that respond favourably to tamoxifen. These findings are particularly significant for the luminal-B ER+ subgroup and may provide useful stratification in future clinical trials evaluating endocrine therapy in ER+BC. 
         [0106]    Furthermore, the inventors compared the outcome of breast cancer patients having the wild-type signature with the outcome of patients having the mutated signature (according to the present invention), when treated with a PI3 kinase (pathway) inhibitor, being 10 mg per day of Everolimus (Afinitor® or RAD001 from Novartis) (an mTOR inhibitor) taken orally. The inventors further selected patients having a ER+ breast cancer and patients having a Her2+ breast cancer and compared the effect of Everolimus in function of the wild-type or mutated signature (according to the present invention). 
         [0000]    Other inhibitors of the PI3K/Akt/mTOR pathway, such as WYE-354, CCI-779 (from wyeth), Temsirolimus, GSK1059615, Deforolimus, KU-0063794, PI-103 and NVP-BEZ235 can be used as well. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
             
             
               
                 (A) 
               
             
          
           
               
                   
                 Nucleotide  
                 Amino acid  
                 Number of cases 
               
               
                 Exon 
                 change 
                 change 
                 (%) 
               
               
                   
               
               
                 20 
                 A3140G 
                 H1047R 
                 29 (91%) 
               
               
                 20 
                 A3150T 
                 H1047L 
                 3 (9%) 
               
               
                 9 
                 G1633A 
                 E545K 
                  7 (50%) 
               
               
                 9 
                 G1624A 
                 E542K 
                  6 (43%) 
               
               
                 9 
                 G1634A 
                 E545G 
                 1 (7%) 
               
               
                 Total 
                   
                   
                  46 (100%) 
               
               
                   
               
             
          
           
               
                 (B) 
               
             
          
           
               
                   
                 Total cases 
                 Mutated  
                 Normal  
                   
               
               
                 Variable 
                 (n = 173) 
                 (n = 45) 
                 (n = 127) 
                 P value 
               
               
                   
               
               
                 Age 
                   
                   
                   
                 0.3 
               
               
                 ≦50 yrs 
                 14 
                  2 (36%) 
                  12 (66%) 
                   
               
               
                 &gt;50 yrs 
                 157 
                 43 (27%) 
                 114 (73%) 
                   
               
               
                 Tumour size 
                   
                   
                   
                 0.057 
               
               
                 T1 ≦ 2 cm 
                 76 
                 15 (20%) 
                  61 (80%) 
                   
               
               
                 T2 &gt; 2 cm 
                 95 
                 30 (32%) 
                  65 (78%) 
                   
               
               
                 Histologic Grade 
                   
                   
                   
                 0.5 
               
               
                 Grade 1 
                 28 
                  7 (25%) 
                  21 (75%) 
                   
               
               
                 Grade 2 
                 80 
                 23 (26%) 
                  57 (74%) 
                   
               
               
                 Grade 3 
                 32 
                  7 (22%) 
                  25 (78%) 
                   
               
               
                 Nodal status 
                   
                   
                   
                 0.5 
               
               
                 Node positive 
                 87 
                 23 (26%) 
                  64 (74%) 
                   
               
               
                 Node negative 
                 83 
                 21 (25%) 
                  62 (75%) 
                   
               
               
                 ER+ molecular subtype * 
                   
                   
                   
                   
               
               
                 Luminal A (GGI low) 
                 87 
                 25 (29%) 
                  62 (71%) 
                 0.3 
               
               
                 Luminal B (GGI hi) 
                 79 
                 17 (22%) 
                  62 (78%) 
               
               
                   
               
               
                 Note 
               
               
                 1) all 173 BC samples were ER+; 2) for some samples, values were missing; 3) for those samples whose gene expression data (n = 161) were available, 41 samples had PIK3CA mutations. 
               
               
                 * see reference LOI ET AL., 2007. 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2a 
               
               
                   
               
               
                   
                   
                   
                 Ratio &gt; 1 =  
                   
                   
               
               
                   
                   
                   
                 up- 
                   
                   
               
               
                   
                 Parametric 
                   
                 regulated in 
                 Affymetrix 
                   
               
               
                 Rank 
                 p-value 
                 FDR 
                 WT 
                 Probe set 
                 Gene symbol 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 8.00E−07 
                 0.02 
                 1.111 
                 203012 x at 
                 RPL23A 
               
               
                 2 
                 2.54E−05 
                 0.14 
                 1.111 
                 208825 x at 
                 RPL23A 
               
               
                 3 
                 3.13E−05 
                 0.14 
                 1.111 
                 222327 x at 
                 OR7E156P 
               
               
                 4 
                 3.97E−05 
                 0.14 
                 1.375 
                 219138 at 
                 RPL14 
               
               
                 5 
                 4.18E−05 
                 0.14 
                 0.524 
                 206994 at 
                 CST4 
               
               
                 6 
                 5.25E−05  
                 0.14 
                 0.2  
                 206378 at 
                 SCGB2A2 
               
               
                 7 
                 6.34E−05  
                 0.14 
                 1.375 
                 208229 at 
                 FGFR2 
               
               
                 8 
                 7.94E−05 
                 0.14 
                 0.75  
                 212377 s at  
                 NOTCH2 
               
               
                 9 
                 8.86E−05 
                 0.14 
                 1.8  
                 204992 s at  
                 PFN2 
               
               
                 10 
                 8.88E−05  
                 0.14 
                 1.375 
                 211406 at 
                 IER3IP1 
               
               
                 11 
                 9.49E−05  
                 0.14 
                 1.111 
                 206447 at 
                 ELA2A 
               
               
                 12 
                 9.50E−05  
                 0.14 
                 1.111 
                 202002 at 
                 ACAA2 
               
               
                 13 
                 9.76E−05 
                 0.14 
                 1.375 
                 211212 s at 
                 ORC5L 
               
               
                 14 
                 9.78E−05 
                 0.14 
                 1.222 
                 218238 at 
                 GTPBP4 
               
               
                 15 
                 0.0001 
                 0.14 
                 1.222 
                 209535 s at 
                   
               
               
                 16 
                 0.0001 
                 0.16 
                 1.833 
                 202431 s at 
                 MYC 
               
               
                 17 
                 0.0001 
                 0.16 
                 0.667 
                 212415 at 
                 SEPT6 
               
               
                 18 
                 0.0001 
                 0.16 
                 1.375 
                 202300 at 
                 HBXIP 
               
               
                 19 
                 0.0001 
                 0.16 
                 1.222 
                 203551 s at  
                 COX11 
               
               
                 20 
                 0.0001 
                 0.16 
                 0.692 
                 202743 at 
                 PIK3R3 
               
               
                 21 
                 0.0001 
                 0.16 
                 0.75  
                 221704 s at 
                 VPS37B 
               
               
                 22 
                 0.0001 
                 0.17 
                 0.733  
                 213109 at 
                 TNIK 
               
               
                 23 
                 0.0002 
                 0.18 
                 1.375 
                 202028 s at 
                   
               
               
                 24 
                 0.0002 
                 0.18 
                 1.625 
                 214051 at 
                 MGC39900 
               
               
                 25 
                 0.0002 
                 0.18 
                 0.833 
                 202215 s at 
                 NFYC 
               
               
                 26 
                 0.0002 
                 0.19 
                 0.75  
                 202443 x at 
                 NOTCH2 
               
               
                 27 
                 0.0002 
                 0.19 
                 1.111  
                 220549 at 
                 FSBP /// RAD54B 
               
               
                 28 
                 0.0002 
                 0.19 
                 0.538 
                 217771 at 
                 GOLPH2 
               
               
                 29 
                 0.0002 
                 0.19 
                 0.909 
                 207801 s at 
                 RNF10 
               
               
                 30 
                 0.0002 
                 0.19 
                 0.692 
                 201288 at 
                 ARHGDIB 
               
               
                 31 
                 0.0002 
                 0.19 
                 0.769 
                 215894 at 
                 PTGDR 
               
               
                 32 
                 0.0002 
                 0.19 
                 0.692  
                 217787 s at 
                 GALNT2 
               
               
                 33 
                 0.0003 
                 0.19 
                 1.375 
                 209046 s at 
                 GABARAPL2 
               
               
                 34 
                 0.0003 
                 0.19 
                 1.714  
                 209185 s at 
                 IRS2 
               
               
                 35 
                 0.0003 
                 0.19 
                 0.692  
                 203128 at 
                 SPTLC2 
               
               
                 36 
                 0.0003 
                 0.19 
                 1.111 
                 211677 x at 
                 IGSF4B 
               
               
                 37 
                 0.0003 
                 0.19 
                 0.212  
                 206799 at 
                 SCGB1D2 
               
               
                 38 
                 0.0003 
                 0.19 
                 1.333 
                 221586 s at 
                 E2F5 
               
               
                 39 
                 0.0003 
                 0.19 
                 0.909  
                 215339 at 
                 NKTR 
               
               
                 40 
                 0.0003 
                 0.19 
                 1.25  
                 222151 s at 
                 Cep63 
               
               
                 41 
                 0.0003 
                 0.19 
                 1.375  
                 216609 at 
                 TXN 
               
               
                 42 
                 0.0003 
                 0.19 
                 1.111  
                 219590 x at 
                 DPH5 
               
               
                 43 
                 0.0004 
                 0.20 
                 1.111 
                 221915 s at 
                 RANBP1 
               
               
                 44 
                 0.0004 
                 0.20 
                 0.833 
                 200058 s at 
                 ASCC3L1 
               
               
                 45 
                 0.0004 
                 0.20 
                 0.833  
                 218815 s at 
                 TMEM51 
               
               
                 46 
                 0.0004 
                 0.20 
                 0.562  
                 211828 s at 
                 TNIK 
               
               
                 47 
                 0.0004 
                 0.20 
                 1.111  
                 218023 s at 
                 FAM53C 
               
               
                 48 
                 0.0004 
                 0.20 
                 1.222  
                 214508 x at 
                 CREM 
               
               
                 49 
                 0.0004 
                 0.20 
                 0.692  
                 220066 at 
                 CARD15 
               
               
                 50 
                 0.0004 
                 0.20 
                 0.909 
                 221205 at 
                   
               
               
                 51 
                 0.0004 
                 0.20 
                 1.375 
                 201171 at 
                 ATP6V0E 
               
               
                 52 
                 0.0004 
                 0.20 
                 1.111  
                 212270 x at 
                 RPL17 
               
               
                 53 
                 0.0005 
                 0.20 
                 0.833 
                 207082 at 
                 CSF1 
               
               
                 54 
                 0.0005 
                 0.20 
                 0.833 
                 216050 at 
                   
               
               
                 55 
                 0.0005 
                 0.20 
                 1.222 
                 218239 s at 
                 GTPBP4 
               
               
                 56 
                 0.0005 
                 0.22 
                 1.222 
                 214553 s at 
                 ARPP-19 
               
               
                 57 
                 0.0006 
                 0.23 
                 1.375  
                 213133 s at 
                 GCSH 
               
               
                 58 
                 0.0006 
                 0.23 
                 0.833 
                 200999 s at 
                 CKAP4 
               
               
                 59 
                 0.0006 
                 0.23 
                 0.667  
                 208502 s at 
                 PITX1 
               
               
                 60 
                 0.0006 
                 0.23 
                 1.222 
                 203565 s at 
                 MNAT1 
               
               
                 61 
                 0.0006 
                 0.23 
                 0.818  
                 212756 s at 
                 UBR2 
               
               
                 62 
                 0.0006 
                 0.23 
                 0.833 
                 210369 at 
                 SWAP70 
               
               
                 63 
                 0.0007 
                 0.24 
                 0.833 
                 219247 s at 
                 ZDHHC14 
               
               
                 64 
                 0.0007 
                 0.25 
                 0.818  
                 203250 at 
                 RBM16 
               
               
                 65 
                 0.0007 
                 0.25 
                 1.375 
                 202481 at 
                 DHRS3 
               
               
                 66 
                 0.0008 
                 0.25 
                 1.25  
                 212519 at 
                 UBE2E1 
               
               
                 67 
                 0.0008 
                 0.25 
                 1.111 
                 202810 at 
                 DRG1 
               
               
                 68 
                 0.0008 
                 0.25 
                 1.111  
                 211952 at 
                 RANBP5 
               
               
                 69 
                 0.0008 
                 0.25 
                 1.375 
                 204807 at 
                 TMEM5 
               
               
                 70 
                 0.0008 
                 0.25 
                 0.909 
                 222115 x at 
                 N-PAC 
               
               
                 71 
                 0.0008 
                 0.25 
                 1.222 
                 205811 at 
                 POLG2 
               
               
                 72 
                 0.0008 
                 0.25 
                 0.75  
                 221041 s at 
                 SLC17A5 
               
               
                 73 
                 0.0008 
                 0.25 
                 0.833 
                 207407 x at 
                 CYP4A11 
               
               
                 74 
                 0.0008 
                 0.25 
                 1    
                 208834 x at 
                 RPL23A 
               
               
                 75 
                 0.0008 
                 0.25 
                 1.111 
                 215741 x at 
                 AKAP8L 
               
               
                 76 
                 0.0009 
                 0.25 
                 0.75  
                 200660 at 
                 S100A11 
               
               
                 77 
                 0.0009 
                 0.25 
                 1.25  
                 218411 s at 
                 MBIP 
               
               
                 78 
                 0.0009 
                 0.25 
                 1.222 
                 210779 x at 
                 SIP1 
               
               
                 79 
                 0.0009 
                 0.25 
                 1.111 
                 212500 at 
                 C10orf22 
               
               
                 80 
                 0.0009 
                 0.25 
                 0.833 
                 208876 s at 
                 PAK2 
               
               
                 81 
                 0.0009 
                 0.25 
                 1.222 
                 220762 s at 
                 GNB1L 
               
               
                   
               
               
                 WT: wild type; FDR: false discovery rate 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2b 
               
               
                   
               
               
                 Probe Set ID 
                 Gene Symbol 
                 Gene Title 
                 Entrez Gene ID 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 202002_at 
                 ACAA2 
                 acetyl-Coenzyme A acyltransferase 2 
                 10449 
               
               
                 215741_x_at 
                 AKAP8L 
                 A kinase (PRKA) anchor protein 8-like 
                 26993 
               
               
                 201288_at 
                 ARHGDIB 
                 Rho GDP dissociation inhibitor (GDI) beta 
                 397 
               
               
                 214553_s_at 
                 ARPP-19 
                 cyclic AMP phosphoprotein, 19 kD 
                 10776 
               
               
                 200058_s_at 
                 ASCC3L1 
                 activating signal cointegrator 1 complex subunit 3-like 1 
                 23020 
               
               
                 201171_at 
                 ATP6V0E1 
                 ATPase, H+ transporting, lysosomal 9 kDa, V0 subunit e1 
                 8992 
               
               
                 219242_at 
                 CEP63 
                 centrosomal protein 63 kDa 
                 80254 
               
               
                 200998_s_at 
                 CKAP4 
                 cytoskeleton-associated protein 4 
                 10970 
               
               
                 203551_s_at 
                 COX11 
                 COX11 homolog, cytochrome c oxidase assembly protein (yeast) 
                 1353 
               
               
                 207630_s_at 
                 CREM 
                 cAMP responsive element modulator 
                 1390 
               
               
                 207082_at 
                 CSF1 
                 colony stimulating factor 1 (macrophage) 
                 1435 
               
               
                 206994_at 
                 CST4 
                 cystatin S 
                 1472 
               
               
                 207407_x_at 
                 CYP4A11 
                 cytochrome P450, family 4, subfamily A, polypeptide 11 
                 1579 
               
               
                 202481_at 
                 DHRS3 
                 dehydrogenase/reductase (SDR family) member 3 
                 9249 
               
               
                 219590_x_at 
                 DPH5 
                 DPH5 homolog ( S.   cerevisiae ) 
                 51611 
               
               
                 202810_at 
                 DRG1 
                 developmentally regulated GTP binding protein 1 
                 4733 
               
               
                 221586_s_at 
                 E2F5 
                 E2F transcription factor 5, p130-binding 
                 1875 
               
               
                 206447_at 
                 ELA2A 
                 elastase 2A 
                 63036 
               
               
                 218023_s_at 
                 FAM53C 
                 family with sequence similarity 53, member C 
                 51307 
               
               
                 208229_at 
                 FGFR2 
                 fibroblast growth factor receptor 2 
                 2263 
               
               
                 209046_s_at 
                 GABARAPL2 
                 GABA(A) receptor-associated protein-like 2 
                 11345 
               
               
                 217787_s_at 
                 GALNT2 
                 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminylt           
                 2590 
               
               
                 213133_s_at 
                 GCSH /// LOC73 
                 glycine cleavage system protein H (aminomethyl carrier) /// similar to Glyc           
                  2653 /// 730107 
               
               
                 220762_s_at 
                 GNB1L 
                 guanine nucleotide binding protein (G protein), beta polypeptide 1-like 
                 54584 
               
               
                 218238_at 
                 GTPBP4 
                 GTP binding protein 4 
                 23560 
               
               
                 211406_at 
                 IER3IP1 
                 immediate early response 3 interacting protein 1 
                 51124 
               
               
                 209184_s_at 
                 IRS2 
                 insulin receptor substrate 2 
                 8660 
               
               
                 218411_s_at 
                 MBIP 
                 MAP3K12 binding inhibitory protein 1 
                 51562 
               
               
                 214051_at 
                 MGC39900 ///           
                 thymosin beta15b /// thymosin-like 8 
                 11013 /// 286527 
               
               
                 203565_s_at 
                 MNAT1 
                 menage a trois homolog 1, cyclin H assembly factor ( Xenopus   laevis ) 
                 4331 
               
               
                 202431_s_at 
                 MYC 
                 v-myc myelocytomatosis viral oncogene homolog (avian) 
                 4609 
               
               
                 202215_s_at 
                 NFYC 
                 nuclear transcription factor Y, gamma 
                 4802 
               
               
                 215339_at 
                 NKTR 
                 natural killer-tumor recognition sequence 
                 4820 
               
               
                 202443_x_at 
                 NOTCH2 
                 Notch homolog 2 ( Drosophila ) 
                 4853 
               
               
                 222115_x_at 
                 N-PAC 
                 cytokine-like nuclear factor n-pac 
                 84656 
               
               
                 222327_x_at 
                 OR7E156P 
                 olfactory receptor, family 7, subfamily E, member 156 pseudogene 
                 283491 
               
               
                 211212_s_at 
                 ORC5L 
                 origin recognition complex, subunit 5-like (yeast) 
                 5001 
               
               
                 208876_s_at 
                 PAK2 
                 p21 protein (Cdc42/Rac)-activated kinase 2 
                 5062 
               
               
                 204992_s_at 
                 PFN2 
                 profilin 2 
                 5217 
               
               
                 202743_at 
                 PIK3R3 
                 phosphoinositide-3-kinase, regulatory subunit 3 (gamma) 
                 8503 
               
               
                 208502_s_at 
                 PITX1 
                 paired-like homeodomain 1 
                 5307 
               
               
                 205811_at 
                 POLG2 
                 polymerase (DNA directed), gamma 2, accessory subunit 
                 11232 
               
               
                 215894_at 
                 PTGDR 
                 prostaglandin D2 receptor (DP) 
                 5729 
               
               
                 221915_s_at 
                 RANBP1 
                 RAN binding protein 1 
                 5902 
               
               
                 203250_at 
                 RBM16 
                 RNA binding motif protein 16 
                 22828 
               
               
                 207801_s_at 
                 RNF10 
                 ring finger protein 10 
                 9921 
               
               
                 219138_at 
                 RPL14 
                 ribosomal protein L14 
                 9045 
               
               
                 212537_x_at 
                 RPL17 
                 ribosomal protein L17 
                 6139 
               
               
                 203012_x_at 
                 RPL23A 
                 ribosomal protein L23a 
                 6147 
               
               
                 200660_at 
                 S100A11 
                 S100 calcium binding protein A11 
                 6282 
               
               
                 206799_at 
                 SCGB1D2 
                 secretoglobin, family 1D, member 2 
                 10647 
               
               
                 206378_at 
                 SCGB2A2 
                 secretoglobin, family 2A, member 2 
                 4250 
               
               
                 210779_x_at 
                 SIP1 
                 survival of motor neuron protein interacting protein 1 
                 8487 
               
               
                 221041_s_at 
                 SLC17A5 
                 solute carrier family 17 (anion/sugar transporter), member 5 
                 26503 
               
               
                 203127_s_at 
                 SPTLC2 
                 serine palmitoyltransferase, long chain base subunit 2 
                 9517 
               
               
                 210369_at 
                 SWAP70 
                 SWAP-70 protein 
                 23075 
               
               
                 204807_at 
                 TMEM5 
                 transmembrane protein 5 
                 10329 
               
               
                 218815_s_at 
                 TMEM51 
                 transmembrane protein 51 
                 55092 
               
               
                 211828_s_at 
                 TNIK 
                 TRAF2 and NCK interacting kinase 
                 23043 
               
               
                 216609_at 
                 TXN 
                 Thioredoxin 
                 7295 
               
               
                 212519_at 
                 UBE2E1 
                 ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog, yeast) 
                 7324 
               
               
                 212756_s_at 
                 UBR2 
                 ubiquitin protein ligase E3 component n-recognin 2 
                 23304 
               
               
                   
               
               
                             indicates data missing or illegible when filed 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
             
               
               
               
               
             
               
             
           
               
                 TABLE 3 
               
               
                   
               
             
             
               
                 (A) 
               
             
          
           
               
                   
                 Univariate 
                   
                 Multivariate 
                   
               
               
                 Factor 
                 HR 
                 P value 
                 HR* 
                 P value 
               
               
                   
               
               
                 Age 
                 1.8 (0.6-5.7) 
                 0.3 
                   
                   
               
               
                 Tumor size 
                 2.9 (1.6-5.0) 
                 0.0002 
                 3.2 (1.3-8.7) 
                 0.01 
               
               
                 Nodal status 
                 2.1 (1.2-3.5) 
                 0.0004 
                 0.9 (0.4-2.3) 
                 0.9 
               
               
                 Histologic grade{circumflex over ( )} 
                 1.8 (1.1-2.6) 
                 0.005 
                   
                   
               
               
                 PIK3CA mutation 
                 0.6 (0.3-1.4) 
                 0.26 
                   
                   
               
               
                 PIK3CA index 
                 0.4 (0.3-0.7) 
                 0.01 
                 0.5 (0.3-0.8) 
                 0.01 
               
               
                 Luminal B vs A 
                 2.2 (1.6-3.0) 
                 0.0000004 
                 2.2 (1.3-3.7) 
                 0.004 
               
               
                 subtype# 
                   
                   
                   
                   
               
               
                   
               
             
          
           
               
                 *Only those factors significant in the Univariate analysis  
               
               
                 were used in the multivariate model. 
               
               
                 {circumflex over ( )}histologic grade was not used in the multivariate model has  
               
               
                 highly correlated to the gene expression grade index (GGI) 
               
               
                 #as defined by the GGI (see LOI ET AL; 2007) 
               
               
                 HR: hazard ratio 
               
               
                 Total patient samples: 305 
               
               
                 (B) 
               
             
          
           
               
                 Factor 
                 Univariate HR 
                 P value 
                 Multivariate HR 
               
               
                   
               
               
                 Age 
                 0.9 (0.6-1.6) 
                 0.8 
                   
               
               
                 Tumor size 
                 1.7 (1.1-2.8) 
                 0.03 
                   
               
               
                 Nodal status 
                 1.0 (0.4-2.7) 
                 0.1 
                   
               
               
                 Histologic grade{circumflex over ( )} 
                 4.2 (2.2-7.8) 
                 0.00000007 
                   
               
               
                 PIK3CA index 
                 0.7 (0.5-0.9) 
                 0.03 
                   
               
               
                 Luminal B vs A 
                 3.0 (1.9-4.6) 
                 0.0000006 
                   
               
               
                 subtype# 
                   
                   
                   
               
               
                   
               
             
          
           
               
                 *Only those factors significant in the Univariate analysis  
               
               
                 were used in the multivariate model. 
               
               
                 {circumflex over ( )}histologic grade was not used in the multivariate model has  
               
               
                 highly correlated to the gene expression grade index (GGI) 
               
               
                 #as defined by the GGI (see LOI ET AL; 2007) 
               
               
                 HR: hazard ratio 
               
               
                 Total patient samples: 425 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Preferred genes associated with PIK3CA mutation 
               
             
          
           
               
                 Probe Set ID 
                 Gene Symbol 
                 Gene Title 
                 Entrez Gene ID 
               
               
                   
               
             
          
           
               
                 212500_at 
                 ADO 
                 2-aminoethanethiol (cysteamine) dioxygenase 
                 84890 
               
               
                 201288_at 
                 ARHGDIB 
                 Rho GDP dissociation inhibitor (GDI) beta 
                 397 
               
               
                 214553_s_at 
                 ARPP-19 
                 cyclic AMP phosphoprotein, 19 kD 
                 10776 
               
               
                 200058_s_at 
                 ASCC3L1 
                 activating signal cointegrator 1 complex subunit 3-like 1 
                 23020 
               
               
                 222151_s_at 
                 CEP63 
                 centrosomal protein 63 kDa 
                 80254 
               
               
                 200999_s_at 
                 CKAP4 
                 cytoskeleton-associated protein 4 
                 10970 
               
               
                 203551_s_at 
                 COX11 
                 COX11 homolog, cytochrome c oxidase assembly  
                 1353 
               
               
                   
                   
                 protein (           
                   
               
               
                 214508_x_at 
                 CREM 
                 cAMP responsive element modulator 
                 1390 
               
               
                 202481_at 
                 DHRS3 
                 dehydrogenase/reductase (SDR family) member 3 
                 9249 
               
               
                 219590_x_at 
                 DPH5 
                 DPH5 homolog ( S.   cerevisiae ) 
                 51611 
               
               
                 221586_s_at 
                 E2F5 
                 E2F transcription factor 5, p130-binding 
                 1875 
               
               
                 218023_s_at 
                 FAM53C 
                 family with sequence similarity 53, member C 
                 51307 
               
               
                 217787_s_at 
                 GALNT2 
                 UDP-N-acetyl-alpha-D-galactosamine:polypeptide  
                 2590 
               
               
                   
                   
                 N-acetyl           
                   
               
               
                 213133_s_at 
                 GCSH /// LOC73           
                 glycine cleavage system protein H (aminomethyl carrier) /// 
                 2653 /// 730107 
               
               
                 217771_at 
                 GOLM1 
                 golgi membrane protein 1 
                 51280 
               
               
                 218238_at 
                 GTPBP4 
                 GTP binding protein 4 
                 23560 
               
               
                 202300_at 
                 HBXIP 
                 hepatitis B virus x interacting protein 
                 10542 
               
               
                 218411_s_at 
                 MBIP 
                 MAP3K12 binding inhibitory protein 1 
                 51562 
               
               
                 203565_s_at 
                 MNAT1 
                 menage a trois homolog 1, cyclin H assembly factor  
                 4331 
               
               
                   
                   
                 (Xeno           
                   
               
               
                 202431_s_at 
                 MYC 
                 v-myc myelocytomatosis viral oncogene homolog (avian) 
                 4609 
               
               
                 202215_s_at 
                 NFYC 
                 nuclear transcription factor Y, gamma 
                 4802 
               
               
                 215339_at 
                 NKTR 
                 natural killer-tumor recognition sequence 
                 4820 
               
               
                 212377_s_at 
                 NOTCH2 
                 Notch homolog 2 ( Drosophila ) 
                 4853 
               
               
                 222115_x_at 
                 N-PAC 
                 cytokine-like nuclear factor n-pac 
                 84656 
               
               
                 211212_s_at 
                 ORC5L 
                 origin recognition complex, subunit 5-like (yeast) 
                 5001 
               
               
                 204992_s_at 
                 PFN2 
                 profilin 2 
                 5217 
               
               
                 202743_at 
                 PIK3R3 
                 phosphoinositide-3-kinase, regulatory subunit 3 (gamma) 
                 8503 
               
               
                 203250_at 
                 RBM16 
                 RNA binding motif protein 16 
                 22828 
               
               
                 200660_at 
                 S100A11 
                 S100 calcium binding protein A11 
                 6282 
               
               
                 206378_at 
                 SCGB2A2 
                 secretoglobin, family 2A, member 2 
                 4250 
               
               
                 210779_x_at 
                 SIP1 
                 survival of motor neuron protein interacting protein 1 
                 8487 
               
               
                 203128_at 
                 SPTLC2 
                 serine palmitoyltransferase, long chain base subunit 2 
                 9517 
               
               
                 218815_s_at 
                 TMEM51 
                 transmembrane protein 51 
                 55092 
               
               
                 211828_s_at 
                 TNIK 
                 TRAF2 and NCK interacting kinase 
                 23043 
               
               
                 212519_at 
                 UBE2E1 
                 ubiquitin-conjugating enzyme E2E 1 (UBC4/5  
                 7324 
               
               
                   
                   
                 homolog, yea           
                   
               
               
                 212756_s_at 
                 UBR2 
                 ubiquitin protein ligase E3 component n-recognin 2 
                 23304 
               
               
                 221704_s_at 
                 VPS37B 
                 vacuolar protein sorting 37 homolog B ( S.   cerevisiae ) 
                 79720 
               
               
                 219247_s_at 
                 ZDHHC14 
                 zinc finger, DHHC-type containing 14 
                 79683 
               
               
                   
               
               
                 ADO is also mentioned as C10orf22; GOLM1 is also mentioned as GOLPH2. 
               
               
                             indicates data missing or illegible when filed 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Alternative PIK 3CA gene signature 
               
               
                 PIK3CA-GS predictor FC &gt; 1.3 p &lt; 0.05 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 Entrez 
                   
                   
               
               
                 rank 
                 p 
                 Fold 
                   
                   
                 Gene 
                 Gene 
                 Coef- 
               
               
                 accord           
                 value 
                 Chang           
                 Probe set 
                 Description 
                 symbol 
                 ID 
                 fic           
                 Cytoband 
               
               
                   
               
             
          
           
               
                 370 
                 0.01 
                 −2.16 
                 204637_at 
                 glycoprotein hormones, alpha polypeptide 
                 CGA 
                 1081 
                 −1 
                 6q12-q21 
               
               
                 325 
                 0.0045 
                 −1.91 
                 209242_at 
                 paternally expressed 3 
                 PEG3 
                 5178 
                 −1 
                 19q13.4 
               
               
                 248 
                 0.0033 
                 −1.79 
                 219109_at 
                 sperm associated antigen 16 
                 SPAG16 
                 79582 
                 −1 
                 2q34 
               
               
                 16 
                 0.0001 
                 −1.78 
                 202431_s_at 
                 v-myc myelocytomatosis viral oncogene 
                 MYC 
                 4609 
                 −1 
                 8q24.21 
               
               
                   
                   
                   
                   
                 homolog           
               
               
                 89 
                 0.0011 
                 −1.78 
                 203987_at 
                 frizzled homolog 6 ( Drosophila ) 
                 FZD6 
                 8323 
                 −1 
                 8q22.3-q23.1 
               
               
                 354 
                 0.0049 
                 −1.75 
                 211548_s_at 
                 hydroxyprostaglandin dehydrogenase 15-(NAD           
                 HPGD 
                 3248 
                 −1 
                 4q34-q35 
               
               
                 537 
                 0.01 
                 −1.74 
                 203914_x_at 
                 hydroxyprostaglandin dehydrogenase 15-(NAD           
                 HPGD 
                 3248 
                 −1 
                 4q34-q35 
               
               
                 9 
                 0.0001 
                 −1.73 
                 204992_s_at 
                 profilin 2 
                 PFN2 
                 5217 
                 −1 
                 3q25.1-q25.2 
               
               
                 207 
                 0.0027 
                 −1.71 
                 204688_at 
                 sarcoglycan, epsilon 
                 SGCE 
                 8910 
                 −1 
                 7q21-q22 
               
               
                 582 
                 0.01 
                 −1.70 
                 221582_at 
                 histone 3, H2a 
                 HIST3H2A 
                 92815 
                 −1 
                 1q42.13 
               
               
                 24 
                 0.0002 
                 −1.70 
                 214051_at 
                 hypothetical protein MGC39900 
                 MGC39900 
                 286527 
                 −1 
                 Xq22.2 
               
               
                 762 
                 0.01 
                 −1.68 
                 218730_s_at 
                 osteoglycin (osteoinductive factor, mimecan) 
                 OGN 
                 4969 
                 −1 
                 9q22 
               
               
                 1206 
                 0.02 
                 −1.66 
                 206110_at 
                 histone 1, H3h 
                 HIST1H3H 
                 3109 
                 −1 
                 — 
               
               
                 150 
                 0.0018 
                 −1.66 
                 202620_s_at 
                 procollagen-lysine, 2-oxogluterate 5-dioxygenas           
                 PLOD2 
                 5352 
                 −1 
                 3q23-q24 
               
               
                 34 
                 0.0003 
                 −1.63 
                 209185_s_at 
                 insulin receptor substrate 2 
                 IRS2 
                 8660 
                 −1 
                 13q34 
               
               
                 621 
                 0.01 
                 −1.62 
                 207156_at 
                 histone 1, H2ag 
                 HIST1H2AG 
                 8969 
                 −1 
                 6p22.1 
               
               
                 936 
                 0.02 
                 −1.60 
                 206070_s_at 
                 EPH receptor A3 
                 EPHA3 
                 2042 
                 −1 
                 3p11.2 
               
               
                 1067 
                 0.02 
                 −1.58 
                 205280_at 
                 glycine receptor, beta 
                 GLRB 
                 2743 
                 −1 
                 4q31.3 
               
               
                 267 
                 0.0035 
                 −1.58 
                 202619_s_at 
                 procollagen-lysine, 2-oxogluterate 5-dioxygenas           
                 PLOD2 
                 5352 
                 −1 
                 3q23-q24 
               
               
                 82 
                 0.0010 
                 −1.57 
                 217963_s_at 
                 nerve growth factor receptor (TNFRSF16) asso           
                 NGFRAP1 
                 27018 
                 −1 
                 Xq22.2 
               
               
                 779 
                 0.01 
                 −1.57 
                 203895_at 
                 phospholipase C, beta 4 
                 PLCB4 
                 5332 
                 −1 
                 20p12 
               
               
                 1290 
                 0.03 
                 −1.53 
                 203913_s_at 
                 hydroxyprostaglandin dehydrogenase 15-(NAD           
                 HPGD 
                 3248 
                 −1 
                 4q34-q35 
               
               
                 183 
                 0.0024 
                 −1.51 
                 204566_at 
                 protein phosphatase 1D magnesium-dependent           
                 PPM1D 
                 8493 
                 −1 
                 17q23.2 
               
               
                 201 
                 0.0026 
                 −1.51 
                 204939_s_at 
                 phospholamban 
                 PLN 
                 5350 
                 −1 
                 6q22.1 
               
               
                 2099 
                 0.05 
                 −1.49 
                 218541_s_at 
                 chromosome 8 open reading frame 4 
                 C8orf4 
                 56892 
                 −1 
                 8p11.2 
               
               
                 202 
                 0.0026 
                 −1.49 
                 209184_s_at 
                 insulin receptor substrate 2 
                 IRS2 
                 8660 
                 −1 
                 13q34 
               
               
                 1730 
                 0.04 
                 −1.49 
                 214469_at 
                 histone 1, H2ae 
                 HIST1H2AE 
                 3012 
                 −1 
                 6p22.2-p21.1 
               
               
                 1322 
                 0.03 
                 −1.49 
                 205279_s_at 
                 glycine receptor, beta 
                 GLRB 
                 2743 
                 −1 
                 4q31.3 
               
               
                 811 
                 0.01 
                 −1.48 
                 201116_s_at 
                 carboxypeptidase E 
                 CPE 
                 1363 
                 −1 
                 4q32.3 
               
               
                 454 
                 0.01 
                 −1.47 
                 204042_at 
                 WAS protein family, member 3 
                 WASF3 
                 10810 
                 −1 
                 13q12 
               
               
                 417 
                 0.01 
                 −1.46 
                 201030_x_at 
                 lactate dehydrogenase B 
                 LDHB 
                 3945 
                 −1 
                 12p12.2-p12.1 
               
               
                 1763 
                 0.04 
                 −1.46 
                 202708_s_at 
                 histone 2, H2be 
                 HIST2H2BE 
                 8349 
                 −1 
                 1q21-q23 
               
               
                 1646 
                 0.04 
                 −1.45 
                 218280_x_at 
                 histone 2, H2aa 
                 HIST2H2AA 
                 8337 
                 −1 
                 1q21.2 
               
               
                 711 
                 0.01 
                 −1.44 
                 203608_at 
                 aldehyde dehydrogenase 5 family, member A1 (           
                 ALDH5A1 
                 7915 
                 −1 
                 6p22.2-p22.3 
               
               
                 558 
                 0.01 
                 −1.44 
                 213564_x_at 
                 lactate dehydrogenase B 
                 LDHB 
                 3945 
                 −1 
                 12p12.2-p12.1 
               
               
                 1555 
                 0.03 
                 −1.44 
                 214290_s_at 
                 histone 2, H2aa 
                 HIST2H2AA 
                 8337 
                 −1 
                 1q21.2 
               
               
                 1742 
                 0.04 
                 −1.43 
                 212154_at 
                 syndecan 2 (heparan sulfate proteoglycan 1, 
                 SDC2 
                 6383 
                 −1 
                 8q22-q23 
               
               
                   
                   
                   
                   
                 cel           
               
               
                 92 
                 0.0011 
                 −1.43 
                 218732_at 
                 Bcl-2 inhibitor of transcription 
                 BIT1 
                 51651 
                 −1 
                 17q23.1 
               
               
                 319 
                 0.0043 
                 −1.43 
                 211578_s_at 
                 ribosomal protein S6 kinase, 70 kDa, 
                 RPS6KB1 
                 6198 
                 −1 
                 17q23.1 
               
               
                   
                   
                   
                   
                 polypeptide           
               
               
                 1050 
                 0.02 
                 −1.42 
                 212859_x_at 
                 metallothionein 1E (functional) 
                 MT1E 
                 4493 
                 −1 
                 16q13 
               
               
                 103 
                 0.0013 
                 −1.42 
                 202630_at 
                 amyloid beta precursor protein (cytoplasmic 
                 APPBP2 
                 10513 
                 −1 
                 17q21-q23 
               
               
                   
                   
                   
                   
                 tail)            
               
               
                 2084 
                 0.05 
                 −1.42 
                 204916_at 
                 receptor (calcitonin) activity modifying protein 1 
                 RAMP1 
                 10267 
                 −1 
                 2q36-q37.1 
               
               
                 250 
                 0.0033 
                 −1.41 
                 209526_s_at 
                 hepatoma-derived growth factor, related protein            
                 HDGFRP3 
                 50810 
                 −1 
                 15q25.2 
               
               
                 994 
                 0.02 
                 −1.41 
                 219312_s_at 
                 zinc finger and BTB domain containing 10 
                 ZBTB10 
                 65986 
                 −1 
                 8q13-q21.1 
               
               
                 1472 
                 0.03 
                 −1.41 
                 206825_at 
                 oxytocin receptor 
                 OXTR 
                 5021 
                 −1 
                 3p25 
               
               
                 1128 
                 0.02 
                 −1.41 
                 212589_at 
                 Sterol carrier protein 2 
                 SCP2 
                 22800 
                 −1 
                 11p15.2 
               
               
                 1172 
                 0.02 
                 −1.41 
                 213793_s_at 
                 homer homolog 1 ( Drosophila ) 
                 HOMER1 
                 9456 
                 −1 
                 5q14.2 
               
               
                 38 
                 0.0004 
                 −1.41 
                 221586_s_at 
                 E2F transcription factor 5, p130-binding 
                 E2F5 
                 1875 
                 −1 
                 8q21.2 
               
               
                 533 
                 0.01 
                 −1.41 
                 213562_s_at 
                 squalene epoxidase 
                 SQLE 
                 6713 
                 −1 
                 8q24.1 
               
               
                 196 
                 0.0026 
                 −1.40 
                 208456_s_at 
                 related RAS viral (r-ras) oncogene homolog 2 
                 RRAS2 
                 22800 
                 −1 
                 11p15.2 
               
               
                 591 
                 0.01 
                 −1.40 
                 209617_s_at 
                 catenin (cadherin-associated protein), delta 2 
                 CTNND2 
                 1501 
                 −1 
                 5p15.2 
               
               
                   
                   
                   
                   
                 (ne           
               
               
                 516 
                 0.01 
                 −1.40 
                 212590_at 
                 related RAS viral (r-ras) oncogene homolog 2 
                 RRAS2 
                 22800 
                 −1 
                 11p15.2 
               
               
                 1160 
                 0.02 
                 −1.40 
                 203510_at 
                 met proto-oncogene (hepatocyte growth factor re           
                 MET 
                 4233 
                 −1 
                 7q31 
               
               
                 1370 
                 0.03 
                 −1.39 
                 200607_s_at 
                 RAD21 homolog ( S. pombe ) 
                 RAD21 
                 5885 
                 −1 
                 8q24 
               
               
                 843 
                 0.01 
                 −1.39 
                 212816_s_at 
                 cystathionine-beta-synthase 
                 CBS 
                 875 
                 −1 
                 21q22.3 
               
               
                 41 
                 0.0004 
                 −1.39 
                 216609_at 
                 Thioredoxin 
                 TXN 
                 7295 
                 −1 
                 9q31 
               
               
                 933 
                 0.02 
                 −1.38 
                 203414_at 
                 monocyte to macrophage differentiation- 
                 MMD 
                 23531 
                 −1 
                 17q 
               
               
                   
                   
                   
                   
                 associate           
               
               
                 923 
                 0.02 
                 −1.38 
                 221194_s_at 
                 PTD016 protein 
                 LOC51136 
                 51136 
                 −1 
                 17q23.1 
               
               
                 23 
                 0.0002 
                 −1.37 
                 202028_s_at 
                   
                   
                 6169 
                 −1 
                 17q23-q25 
               
               
                 309 
                 0.0041 
                 −1.37 
                 210976_s_at 
                 phosphofructokinase, muscle 
                 PFKM 
                 5213 
                 −1 
                 12q13.3 
               
               
                 1238 
                 0.02 
                 −1.37 
                 203685_at 
                 B-cell CLL/lymphoma 2 
                 BCL2 
                 596 
                 −1 
                 18q21.33| 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 18q21.3 
               
               
                 1419 
                 0.03 
                 −1.37 
                 214519_s_at 
                 relaxin 2 
                 RLN2 
                 6019 
                 −1 
                 9p24.1 
               
               
                 251 
                 0.0033 
                 −1.37 
                 210389_x_at 
                 tibulin, delta 1 
                 TUBD1 
                 51174 
                 −1 
                 17q23.1 
               
               
                 1137 
                 0.02 
                 −1.36 
                 204237_at 
                 GULP, engulfment adaptor PTB domain containin           
                 GULP1 
                 51454 
                 −1 
                 2q32.3-q33 
               
               
                 51 
                 0.0005 
                 −1.36 
                 201171_at 
                 ATPase, H+ transporting, lysosomal 9 kDa, V0 
                 ATP6V0E 
                 8992 
                 −1 
                 5q35.1 
               
               
                   
                   
                   
                   
                 s           
               
               
                 639 
                 0.01 
                 −1.36 
                 205741_s_at 
                 dystrobrevin, alpha 
                 DTNA 
                 1837 
                 −1 
                 18q12 
               
               
                 1757 
                 0.04 
                 −1.36 
                 209292_at 
                 Inhibitor of DNA binding 4, dominant negative he           
                 ID4 
                 3400 
                 −1 
                 6p22-p21 
               
               
                 1254 
                 0.02 
                 −1.36 
                 208078_s_at 
                 SNF1-like kinase /// SNF1-like kinase 
                 SNF1LK 
                 150094 
                 −1 
                 21q22.3 
               
               
                 753 
                 0.01 
                 −1.36 
                 208920_at 
                 sorcin 
                 SRI 
                 6717 
                 −1 
                 7q21.1 
               
               
                 7 
                 0.0001 
                 −1.35 
                 208229_at 
                 fibroblast growth factor receptor 2 (bacteria-expr           
                 FGFR2 
                 2263 
                 −1 
                 10q26 
               
               
                 715 
                 0.01 
                 −1.35 
                 36711_at 
                 v-maf musculoaponeurotic fibrosarcoma oncoge           
                 MAFF 
                 23764 
                 −1 
                 22q13.1 
               
               
                 1340 
                 0.03 
                 −1.35 
                 205308_at 
                 chromosome 8 open reading frame 70 
                 C8orf70 
                 51101 
                 −1 
                 8q21.12 
               
               
                 414 
                 0.01 
                 −1.35 
                 202353_s_at 
                 proteasome (prosome, macropain) 26S subunit,            
                 PSMD12 
                 5718 
                 −1 
                 17q24.2 
               
               
                 1637 
                 0.04 
                 −1.35 
                 204348_s_at 
                 adenylate kinase 3-like 1 
                 AK3L1 
                 205 
                 −1 
                 1p31.3 
               
               
                 130 
                 0.0015 
                 −1.35 
                 218597_s_at 
                 chromosome 10 open reading frame 70 
                 C10orf70 
                 55847 
                 −1 
                 10q21.1 
               
               
                 871 
                 0.02 
                 −1.35 
                 205013_s_at 
                 adenosine A2a receptor 
                 ADORA2A 
                 135 
                 −1 
                 22q11.23 
               
               
                 662 
                 0.01 
                 −1.35 
                 217975_at 
                 WW domain binding protein 5 
                 WBP5 
                 51186 
                 −1 
                 Xq22.2 
               
               
                 968 
                 0.02 
                 −1.35 
                 202342_s_at 
                 tripartite motif-containing 2 
                 TRIM2 
                 23321 
                 −1 
                 4q31.3 
               
               
                 477 
                 0.01 
                 −1.34 
                 201946_s_at 
                 chaperonin containing TCP1, subunit 2 (beta) 
                 CCT2 
                 10576 
                 −1 
                 12q15 
               
               
                 4 
                 0.0000 
                 −1.34 
                 219138_at 
                 ribosomal protein L14 
                 RPL14 
                 9045 
                 −1 
                 3p22-p21.2 
               
               
                 1695 
                 0.04 
                 −1.34 
                 220147_s_at 
                 family wtlh sequence similarity 60, member A 
                 FAM60A 
                 58516 
                 −1 
                 12p11 
               
               
                 1009 
                 0.02 
                 −1.34 
                 210761_s_at 
                 growth factor receptor-bound protein 7 
                 GRB7 
                 2886 
                 −1 
                 17q12 
               
               
                 574 
                 0.01 
                 −1.34 
                 205047_s_at 
                 asparagine synthetase 
                 ASNS 
                 440 
                 −1 
                 7q21.3 
               
               
                 1613 
                 0.03 
                 −1.34 
                 220145_at 
                 ASAP 
                 FLJ21159 
                 79884 
                 −1 
                 4q32.1 
               
               
                 1077 
                 0.02 
                 −1.34 
                 221523_s_at 
                 Ras-related GTP binding D 
                 RRAGD 
                 58528 
                 −1 
                 6q15-q16 
               
               
                 10 
                 0.0001 
                 −1.34 
                 211406_at 
                 immediate early response 3 interacting protein 1 
                 IER3IP1 
                 51124 
                 −1 
                 18q12 
               
               
                 1902 
                 0.04 
                 −1.34 
                 204235_s_at 
                 GULP, engulfment adaptor PTB domain containin           
                 GULP1 
                 51454 
                 −1 
                 2q32.3-q33 
               
               
                 1420 
                 0.03 
                 −1.33 
                 205321_at 
                 eukaryotic translation initiation factor 2, subunit 
                 EIF2S3 
                 1968 
                 −1 
                 Xp22.2-p22.1 
               
               
                   
                   
                   
                   
                 3            
               
               
                 1017 
                 0.02 
                 −1.33 
                 212690_at 
                 DDHD domain containing 2 
                 DDHD2 
                 23259 
                 −1 
                 8p11.23 
               
               
                 1922 
                 0.04 
                 −1.33 
                 219974_x_at 
                 enoyl Coenzyme A hydratase domain containing           
                 ECHDC1 
                 55862 
                 −1 
                 6q22.33 
               
               
                 1437 
                 0.03 
                 −1.33 
                 201161_s_at 
                 cold shock domain protein A 
                 CSDA 
                 8531 
                 −1 
                 12p13.1 
               
               
                 745 
                 0.01 
                 −1.33 
                 209849_s_at 
                 RAD51 homolog C ( S. cerevisiae ) 
                 RAD51C 
                 5889 
                 −1 
                 17q22-q23 
               
               
                 230 
                 0.0030 
                 −1.33 
                 205961_s_at 
                 PC4 and SFRS1 interacting protein 1 
                 PSIP1 
                 11168 
                 −1 
                 9p22.3 
               
               
                 13 
                 0.0001 
                 −1.33 
                 211212_s_at 
                 origin recognition complex, subunit 5-like (yeast) 
                 ORC5L 
                 5001 
                 −1 
                 7q22.1 
               
               
                 1884 
                 0.04 
                 −1.33 
                 221521_s_at 
                 DNA replication complex GINS protein PSF2 
                 Pfs2 
                 51659 
                 −1 
                 16q24.1 
               
               
                 228 
                 0.0030 
                 −1.33 
                 221326_s_at 
                 tubulin, delta 1 
                 TUBD1 
                 51174 
                 −1 
                 17q23.1 
               
               
                 767 
                 0.01 
                 −1.32 
                 213353_at 
                 ATP-binding cassette, sub-family A (ABC1), men           
                 ABCA5 
                 23461 
                 −1 
                 17q24.3 
               
               
                 184 
                 0.0024 
                 −1.32 
                 205361_s_at 
                 prefoldin 4 
                 PFDN4 
                 5203 
                 −1 
                 20q13.2 
               
               
                 336 
                 0.0047 
                 −1.32 
                 205543_at 
                 heat shock 70 kDa protein 4-like 
                 HSPA4L 
                 22824 
                 −1 
                 4q28 
               
               
                 1207 
                 0.02 
                 −1.32 
                 205573_s_at 
                 sorting nexin 7 
                 SNX7 
                 51375 
                 −1 
                 1p21.3 
               
               
                 60 
                 0.0006 
                 −1.32 
                 203565_s_at 
                 menage a trois 1 (CAK assembly factor) 
                 MNAT1 
                 4331 
                 −1 
                 14q23 
               
               
                 828 
                 0.01 
                 −1.32 
                 218277_s_at 
                 DEAH (Asp-Glu-Ala-His) box polypeptide 40 
                 DHX40 
                 79665 
                 −1 
                 17q23.1 
               
               
                 1411 
                 0.03 
                 −1.32 
                 201117_s_at 
                 carboxypeptidase E 
                 CPE 
                 1363 
                 −1 
                 4q32.3 
               
               
                 1471 
                 0.03 
                 −1.31 
                 213548_s_at 
                 hypothetical protein H41 
                 H41 
                 55573 
                 −1 
                 3q22.1 
               
               
                 590 
                 0.01 
                 −1.31 
                 218514_at 
                 hypothetical protein FLJ10587 
                 FLJ10587 
                 55181 
                 −1 
                 17q22 
               
               
                 273 
                 0.0036 
                 −1.31 
                 205078_at 
                 phosphatidylinositol glycan, class F 
                 PIGF 
                 5281 
                 −1 
                 2p21-p16 
               
               
                 299 
                 0.0040 
                 −1.31 
                 204940_at 
                 phospholamban 
                 PLN 
                 5350 
                 −1 
                 6q22.1 
               
               
                 87 
                 0.0011 
                 −1.31 
                 221943_x_at 
                 Ribosomal protein L38 
                 RPL38 
                 6169 
                 −1 
                 17q23-q25 
               
               
                 56 
                 0.0006 
                 −1.31 
                 214553_s_at 
                 cyclic AMP phosphoprotein, 19 kD 
                 ARPP-19 
                 10776 
                 −1 
                 15q21.2 
               
               
                 930 
                 0.02 
                 −1.31 
                 216693_x_at 
                 hepatoma-derived growth factor, related protein            
                 HDGFRP3 
                 50810 
                 −1 
                 15q25.2 
               
               
                 820 
                 0.01 
                 1.31 
                 208729_x_at 
                 major histocompatibility complex, class I, B 
                 HLA-B 
                 3106 
                 1 
                 6p21.3 
               
               
                 1259 
                 0.02 
                 1.31 
                 218788_s_at 
                 SET and MYND domain containing 3 
                 SMYD3 
                 64754 
                 1 
                 1q44 
               
               
                 449 
                 0.01 
                 1.31 
                 203888_at 
                 thrombomodulin 
                 THBD 
                 7056 
                 1 
                 20p11.2 
               
               
                 949 
                 0.02 
                 1.32 
                 216250_s_at 
                 leupaxin 
                 LPXN 
                 9404 
                 1 
                 11q12.1 
               
               
                 2127 
                 0.05 
                 1.32 
                 202149_at 
                 neural precursor cell expressed, developmentall           
                 NEDD9 
                 4739 
                 1 
                 6p25-p24 
               
               
                 1288 
                 0.03 
                 1.32 
                 38241_at 
                 butyrophilin, subfamily 3, member A3 
                 BTN3A3 
                 10384 
                 1 
                 6p21.3 
               
               
                 1454 
                 0.03 
                 1.32 
                 213478_at 
                 kazrin 
                 KIAA1026 
                 23254 
                 1 
                 1p36.21 
               
               
                 891 
                 0.02 
                 1.32 
                 215536_at 
                 major histocompatibility complex, class II, DQ bet           
                 HLA-DQB2 
                 3120 
                 1 
                 6p21 
               
               
                 709 
                 0.01 
                 1.32 
                 218313_s_at 
                 UDP-N-acetyl-alpha-D-galactosamine:polypepti           
                 GALNT7 
                 51809 
                 1 
                 4q31.1 
               
               
                 90 
                 0.0011 
                 1.32 
                 207291_at 
                 proline rich Gla (G-carboxyglutamic acid) 4 (tran           
                 PRRG4 
                 79056 
                 1 
                 11p13 
               
               
                 734 
                 0.01 
                 1.32 
                 205757_at 
                 ectonucleoside triphosphate diphosphohydrolase           
                 ENTPD5 
                 957 
                 1 
                 14q24 
               
               
                 119 
                 0.0014 
                 1.32 
                 203236_s_at 
                 lectin, galactoside-binding, soluble, 9 (galectin 9) 
                 LGALS9 
                 3965 
                 1 
                 17q11.2 
               
               
                 1894 
                 0.04 
                 1.32 
                 210538_s_at 
                 baculoviral IAP repeat-containing 3 
                 BIRC3 
                 330 
                 1 
                 11q22 
               
               
                 556 
                 0.01 
                 1.32 
                 212256_at 
                 UDP-N-acetyl-alpha-D-galactosamine:polypepti           
                 GALNT10 
                 55568 
                 1 
                 5q33.2 
               
               
                 428 
                 0.01 
                 1.32 
                 211944_at 
                 BAT2 domain containing 1 
                 BAT2D1 
                 23215 
                 1 
                 1q23.3 
               
               
                 393 
                 0.01 
                 1.33 
                 206662_at 
                 glutaredoxin (thioltransferase) 
                 GLRX 
                 2745 
                 1 
                 5q14 
               
               
                 1484 
                 0.03 
                 1.33 
                 217838_s_at 
                 Enah/Vasp-like 
                 EVL 
                 51466 
                 1 
                 14q32.2 
               
               
                 2130 
                 0.05 
                 1.33 
                 209488_s_at 
                 RNA binding protein with multiple splicing 
                 RBPMS 
                 11030 
                 1 
                 8p12-p11 
               
               
                 481 
                 0.01 
                 1.33 
                 210835_s_at 
                 C-terminal binding protein 2 
                 CTBP2 
                 1488 
                 1 
                 10q26.13 
               
               
                 482 
                 0.01 
                 1.34 
                 212841_s_at 
                 PTPRF interacting protein, binding protein 2 (lipr           
                 PPFIBP2 
                 8495 
                 1 
                 11p15.4 
               
               
                 221 
                 0.0028 
                 1.34 
                 209788_s_at 
                 type 1 tumor necrosis factor receptor shedding a           
                 ARTS-1 
                 51752 
                 1 
                 5q15 
               
               
                 2004 
                 0.05 
                 1.34 
                 212240_s_at 
                 phosphoinositide-3-kinase, regulatory subunit 1 
                 PIK3R1 
                 5295 
                 1 
                 5q13.1 
               
               
                 701 
                 0.01 
                 1.34 
                 203509_at 
                 sortilin-related receptor, L(DLR class) A repeats-           
                 SORL1 
                 6653 
                 1 
                 11q23.2-q24.2 
               
               
                 487 
                 0.01 
                 1.34 
                 213931_at 
                 inhibitor of DNA binding 2, dominant negative he           
                 ID2 /// 
                 3398 
                 1 
                 2p25 /// 
               
               
                   
                   
                   
                   
                   
                 ID2B 
                   
                   
                 3p14.2 
               
               
                 156 
                 0.0019 
                 1.34 
                 211621_at 
                   
                 AR 
                 367 
                 1 
                 Xq11.2-q12 
               
               
                 436 
                 0.01 
                 1.34 
                 222075_s_at 
                 ornithine decarboxylase antizyme 3 
                 OAZ3 
                 51686 
                 1 
                 1q21.3 
               
               
                 403 
                 0.01 
                 1.34 
                 201367_s_at 
                 zinc finger protein 36, C3H type-like 2 
                 ZFP36L2 
                 678 
                 1 
                 2p22.3-p21 
               
               
                 1382 
                 0.03 
                 1.34 
                 217478_s_at 
                 major histocompatibility complex, class II, DM alp           
                 HLA-DMA 
                 3108 
                 1 
                 6p21.3 
               
               
                 72 
                 0.0009 
                 1.35 
                 221041_s_at 
                 solute carrier family 17 (anion/sugar transporter)            
                 SLC17A5 
                 26503 
                 1 
                 6q14-q15 
               
               
                 1788 
                 0.04 
                 1.35 
                 203474_at 
                 IQ motif containing GT Pase activating protein 2 
                 IQGAP2 
                 10788 
                 1 
                 5q13.3 
               
               
                 1957 
                 0.04 
                 1.35 
                 209522_s_at 
                 carnitine acetyltransferase 
                 CRAT 
                 1384 
                 1 
                 9q34.1 
               
               
                 35 
                 0.0003 
                 1.35 
                 203128_at 
                 serine palmitoyltransferase, long chain base sub           
                 SPTLC2 
                 9517 
                 1 
                 14q24.3-q31 
               
               
                 534 
                 0.01 
                 1.35 
                 210139_s_at 
                 peripheral myelin protein 22 
                 PMP22 
                 5376 
                 1 
                 17p12-p11.2 
               
               
                 758 
                 0.01 
                 1.35 
                 204137_at 
                 transmembrane 7 superfamily member 1 (upreg           
                 TM7SF1 
                 7107 
                 1 
                 1q42-q43 
               
               
                 148 
                 0.0018 
                 1.35 
                 269916_at 
                 dehydrogenase E1 and transketolase domain co           
                 DHTKD1 
                 55526 
                 1 
                 10p14 
               
               
                 208 
                 0.0027 
                 1.35 
                 202421_at 
                 immunoglobulin superfamily, member 3 
                 IGSF3 
                 3321 
                 1 
                 1p13 
               
               
                 1346 
                 0.03 
                 1.35 
                 209276_s_at 
                 glutaredoxin (thioltransferase) 
                 GLRX 
                 2745 
                 1 
                 5q14 
               
               
                 1173 
                 0.02 
                 1.35 
                 201340_s_at 
                 ectodermal-neural cortex (with BTB-like domain)            
                 ENC1 
                 8507 
                 1 
                 5q12-q13.3 
               
               
                 976 
                 0.02 
                 1.35 
                 211366_x_at 
                 caspase 1, apoptosis-related cysteine peptidase            
                 CASP1 
                 834 
                 1 
                 11q23 
               
               
                 824 
                 0.01 
                 1.35 
                 205379_at 
                 carbonyl reductase 3 
                 CBR3 
                 874 
                 1 
                 21q22.2 
               
               
                 1451 
                 0.03 
                 1.36 
                 201976_s_at 
                 myosin X 
                 MYO10 
                 4651 
                 1 
                 5p15.1-p14.3 
               
               
                 798 
                 0.01 
                 1.36 
                 202336_s_at 
                 peptidylglycine alpha-amidating monooxygenase           
                 PAM 
                 5066 
                 1 
                 5q14-q21 
               
               
                 2028 
                 0.05 
                 1.36 
                 202709_at 
                 fibromodulin 
                 FMOD 
                 2331 
                 1 
                 1q32 
               
               
                 423 
                 0.01 
                 1.36 
                 204875_s_at 
                 GDP-mannose 4,6-dehydratase 
                 GMDS 
                 2762 
                 1 
                 6p25 
               
               
                 421 
                 0.01 
                 1.36 
                 218322_s_at 
                 acyl-CoA synthetase long-chain family member 5           
                 ACSL5 
                 51703 
                 1 
                 10q25.1-q25.2 
               
               
                 348 
                 0.0048 
                 1.36 
                 221042_s_at 
                 calmin (calponin-like, transmembrane) 
                 CLMN 
                 79789 
                 1 
                 14q32.13 
               
               
                 247 
                 0.0033 
                 1.36 
                 202638_s_at 
                 intercellular adhesion molecule 1 (CD54), human           
                 ICAM1 
                 3383 
                 1 
                 19p13.3-p13.2 
               
               
                 8 
                 0.0001 
                 1.36 
                 212377_s_at 
                 Notch homolog 2 ( Drosophila ) 
                 NOTCH2 
                 4853 
                 1 
                 1p13-p11 
               
               
                 1258 
                 0.02 
                 1.36 
                 204017_at 
                 KDEL (Lys-Asp-Glu-Leu) endoplasmic reticulum            
                 KDELR3 
                 11015 
                 1 
                 22q13.1 
               
               
                 102 
                 0.0013 
                 1.36 
                 205248_at 
                 chromosome 21 open reading frame 5 
                 C21orf5 
                 9980 
                 1 
                 21q22.2 
               
               
                 1233 
                 0.02 
                 1.36 
                 203887_s_at 
                 thrombomodulin 
                 THBD 
                 7056 
                 1 
                 20p11.2 
               
               
                 529 
                 0.01 
                 1.37 
                 210732_s_at 
                 lectin, galactoside-binding, soluble, 8 (galectin 8) 
                 LGALS8 
                 3964 
                 1 
                 1q42-q43 
               
               
                 327 
                 0.0045 
                 1.37 
                 213462_at 
                 neuronal PAS domain protein 2 
                 NPAS2 
                 4862 
                 1 
                 2q11.2 
               
               
                 1908 
                 0.04 
                 1.37 
                 210319_x_at 
                 msh homeo box homolog 2 ( Drosophila ) 
                 MSX2 
                 4488 
                 1 
                 5q34-q35 
               
               
                 999 
                 0.02 
                 1.37 
                 201369_s_at 
                 zinc finger protein 36, C3H type-like 2 
                 ZFP36L2 
                 678 
                 1 
                 2p22.3-p21 
               
               
                 495 
                 0.01 
                 1.37 
                 208949_s_at 
                 lectin, galactoside-binding, soluble, 3 (galectin 3) 
                 LGALS3 /// 
                 3958 
                 1 
                 14q21-q22 
               
               
                   
                   
                   
                   
                   
                 GALIG 
               
               
                 769 
                 0.01 
                 1.37 
                 209970_x_at 
                 caspase 1, apoptosis-related cysteine peptidase 
                 CASP1 
                 834 
                 1 
                 11q23 
               
               
                 986 
                 0.02 
                 1.37 
                 204654_s_at 
                 transcription factor AP-2 alpha (activating enhan           
                 TFAP2A 
                 7020 
                 1 
                 6p24 
               
               
                 32 
                 0.0003 
                 1.38 
                 217787_s_at 
                 UDP-N-acetyl-alpha-D-galactosamine:polypepti           
                 GALNT2 
                 2590 
                 1 
                 1q41-q42 
               
               
                 396 
                 0.01 
                 1.38 
                 212875_s_at 
                 chromosome 21 open reading frame 25 
                 C21orf25 
                 25966 
                 1 
                 21q22.3 
               
               
                 1666 
                 0.04 
                 1.38 
                 217744_s_at 
                 PERP, TP53 apoptosis effector 
                 PERP 
                 64065 
                 1 
                 6q24 
               
               
                 729 
                 0.01 
                 1.38 
                 41644_at 
                 SAM and SH3 domain containing 1 
                 SASH1 
                 23328 
                 1 
                 6q24.3 
               
               
                 1081 
                 0.02 
                 1.38 
                 204160_s_at 
                 ectonucleotide pyrophosphatase/phosphodiester           
                 ENPP4 
                 22875 
                 1 
                 6p21.1 
               
               
                 1125 
                 0.02 
                 1.38 
                 201242_s_at 
                 AT Pase, Na+/K+ transporting, beta 1 polypeptid           
                 ATP1B1 
                 481 
                 1 
                 1q24 
               
               
                 467 
                 0.01 
                 1.39 
                 212249_at 
                 phosphoinositide-3-kinase, regulatory subunit 1 
                 PIK3R1 
                 5295 
                 1 
                 5q13.1 
               
               
                 297 
                 0.0039 
                 1.39 
                 213418_at 
                 heat shock 70 kDa protein 6 (HSP70B′) 
                 HSPA6 
                 3310 
                 1 
                 1q23 
               
               
                 827 
                 0.01 
                 1.39 
                 202962_at 
                 kinesin family member 13B 
                 KIF13B 
                 23303 
                 1 
                 8p12 
               
               
                 290 
                 0.0039 
                 1.39 
                 222258_s_at 
                 SH3-domain binding protein 4 
                 SH3BP4 
                 23677 
                 1 
                 2q37.1-q37.2 
               
               
                 551 
                 0.01 
                 1.39 
                 214130_s_at 
                 phosphodiesterase 4D interacting protein (myom           
                 PDE4DIP 
                 9659 
                 1 
                 1q12 
               
               
                 1655 
                 0.04 
                 1.39 
                 204365_s_at 
                 chromosome 2 open reading frame 23 
                 C2orf23 
                 65055 
                 1 
                 2p11.2 
               
               
                 1533 
                 0.03 
                 1.39 
                 205668_at 
                 lymphocyte antigen 75 
                 LY75 
                 4065 
                 1 
                 2q24 
               
               
                 143 
                 0.0017 
                 1.39 
                 218451_at 
                 CUB domain containing protein 1 
                 CDCP1 
                 64866 
                 1 
                 3p21.31 
               
               
                 948 
                 0.02 
                 1.40 
                 205225_at 
                 estrogen receptor 1 
                 ESR1 
                 2099 
                 1 
                 6q25.1 
               
               
                 610 
                 0.01 
                 1.40 
                 211965_at 
                 zinc finger protein 36, C3H type-like 1 
                 ZFP36L1 
                 677 
                 1 
                 14q22-q24 
               
               
                 511 
                 0.01 
                 1.40 
                 213308_at 
                 SH3 and multiple ankyrin repeat domains 2 
                 SHANK2 
                 22941 
                 1 
                 11q13.3-q13.4 
               
               
                 1018 
                 0.02 
                 1.40 
                 208006_at 
                 forkhead box I1 
                 FOXI1 
                 2299 
                 1 
                 5q34 
               
               
                 1374 
                 0.03 
                 1.40 
                 206191_at 
                 ectonucleoside triphosphate diphosphohydrolase           
                 ENTPD3 
                 956 
                 1 
                 3p21.3 
               
               
                 950 
                 0.02 
                 1.40 
                 220108_at 
                 guanine nucleotide binding protein (G protein), a           
                 GNA14 
                 9630 
                 1 
                 9q21 
               
               
                 964 
                 0.02 
                 1.40 
                 211368_s_at 
                 caspase 1, apoptosis-related cysteine peptidase 
                 CASP1 
                 834 
                 1 
                 11q23 
               
               
                 100 
                 0.0013 
                 1.40 
                 208683_at 
                 calpain 2, (m/II) large subunit 
                 CAPN2 
                 824 
                 1 
                 1q41-q42 
               
               
                 1927 
                 0.04 
                 1.41 
                 214295_at 
                 KIAA0485 protein 
                 KIAA0485 
                 57235 
                 1 
                 — 
               
               
                 561 
                 0.01 
                 1.41 
                 39549_at 
                 neuronal PAS domain protein 2 
                 NPAS2 
                 4862 
                 1 
                 2q11.2 
               
               
                 236 
                 0.0031 
                 1.41 
                 214129_at 
                 Phosphodiesterase 4D interacting protein (myom           
                 PDE4DIP 
                 9659 
                 1 
                 1q12 
               
               
                 963 
                 0.02 
                 1.41 
                 204446_s_at 
                 arachidonate 5-lipoxygenase 
                 ALOX5 
                 240 
                 1 
                 10q11.2 
               
               
                 317 
                 0.0043 
                 1.41 
                 206011_at 
                 caspase 1, apoptosis-related cysteine peptidase 
                 CASP1 
                 834 
                 1 
                 11q23 
               
               
                 803 
                 0.01 
                 1.41 
                 205879_x_at 
                 ret proto-oncogene (multiple endocrine neoplasi           
                 RET 
                 5979 
                 1 
                 10q11.2 
               
               
                 49 
                 0.0005 
                 1.41 
                 220066_at 
                 caspase recruitment domain family, member 15 
                 CARD15 
                 64127 
                 1 
                 16q21 
               
               
                 1151 
                 0.02 
                 1.42 
                 221558_s_at 
                 lymphoid enhancer-binding factor 1 
                 LEF1 
                 51176 
                 1 
                 4q23-q25 
               
               
                 480 
                 0.01 
                 1.42 
                 211110_s_at 
                 androgen receptor (dihydrotestosterone recepto           
                 AR 
                 367 
                 1 
                 Xq11.2-q12 
               
               
                 1594 
                 0.03 
                 1.42 
                 201641_at 
                 bone marrow stromal cell antigen 2 
                 BST2 
                 684 
                 1 
                 19p13.2 
               
               
                 416 
                 0.01 
                 1.42 
                 208997_s_at 
                 uncoupling protein 2 (mitochondrial, proton carri           
                 UCP2 
                 7351 
                 1 
                 11q13 
               
               
                 306 
                 0.0041 
                 1.43 
                 218273_s_at 
                 protein phosphatase 2C, magnesium-dependent           
                 PPM2C 
                 54704 
                 1 
                 8q22.1 
               
               
                 22 
                 0.0002 
                 1.43 
                 213109_at 
                 TRAF2 and NCK interacting kinase 
                 TNIK 
                 23043 
                 1 
                 3q26.2-q26.31 
               
               
                 998 
                 0.02 
                 1.43 
                 203221_at 
                 transducin-like enhancer of split 1 (E(sp1) homol           
                 TLE1 
                 7088 
                 1 
                 9q21.32 
               
               
                 1840 
                 0.04 
                 1.43 
                 212551_at 
                 CAP, adenylate cyclase-associated protein, 2 (y           
                 CAP2 
                 10486 
                 1 
                 6p22.3 
               
               
                 2023 
                 0.05 
                 1.44 
                 200606_at 
                 desmoplakin 
                 DSP 
                 1832 
                 1 
                 6p24 
               
               
                 110 
                 0.0013 
                 1.44 
                 201482_at 
                 quiescin Q6 
                 QSCN6 
                 5768 
                 1 
                 1q24 
               
               
                 341 
                 0.0047 
                 1.44 
                 218918_at 
                 mannosidase, alpha, class 1C, member 1 
                 MAN1C1 
                 57134 
                 1 
                 1p35 
               
               
                 892 
                 0.02 
                 1.45 
                 214329_x_at 
                 Tumor necrosis factor (ligand) superfamily, memb           
                 TNFSF10 
                 8743 
                 1 
                 3q26 
               
               
                 719 
                 0.01 
                 1.45 
                 213236_at 
                 SAM and SH3 domain containing 1 
                 SASH1 
                 23328 
                 1 
                 6q24.3 
               
               
                 168 
                 0.0021 
                 1.45 
                 218084_x_at 
                 FXYD domain containing ion transport regulator            
                 FXYD5 
                 53827 
                 1 
                 19q12-q13.1 
               
               
                 386 
                 0.01 
                 1.46 
                 202017_at 
                 epoxide hydrolase 1, microsomal (xenobiotic) 
                 EPHX1 
                 2052 
                 1 
                 1q42.1 
               
               
                 17 
                 0.0001 
                 1.46 
                 212415_at 
                 septin 6 
                 40062 
                 23157 
                 1 
                 Xq24 
               
               
                 1672 
                 0.04 
                 1.46 
                 212543_at 
                 absent in melanoma 1 
                 AIM1 
                 202 
                 1 
                 6q21 
               
               
                 479 
                 0.01 
                 1.47 
                 202286_s_at 
                 tumor-associated calcium signal transducer 2 
                 TACSTD2 
                 4070 
                 1 
                 1p32-p31 
               
               
                 232 
                 0.0030 
                 1.47 
                 209619_at 
                 CD74 antigen (invariant polypeptide of major hist           
                 CD74 
                 972 
                 1 
                 5q32 
               
               
                 249 
                 0.0033 
                 1.47 
                 204352_at 
                 TNF receptor-associated factor 5 
                 TRAF5 
                 7188 
                 1 
                 1q32 
               
               
                 219 
                 0.0028 
                 1.47 
                 214791_at 
                 hypothetical protein BC004921 
                 LOC93349 
                 93349 
                 1 
                 2q37.1 
               
               
                 20 
                 0.0002 
                 1.47 
                 202743_at 
                 phosphoinositide-3-kinase, regulatory subunit 3            
                 PIK3R3 
                 8503 
                 1 
                 1p34.1 
               
               
                 1140 
                 0.02 
                 1.47 
                 205472_s_at 
                 dachshund homolog 1 ( Drosophila ) 
                 DACH1 
                 1602 
                 1 
                 13q22 
               
               
                 356 
                 0.00 
                 1.48 
                 204983_s_at 
                 glypican 4 
                 GPC4 
                 2239 
                 1 
                 Xq26.1 
               
               
                 613 
                 0.01 
                 1.49 
                 213107_at 
                 TRAF2 and NCK interacting kinase 
                 TNIK 
                 23043 
                 1 
                 3q26.2-q26.31 
               
               
                 30 
                 0.0003 
                 1.49 
                 201288_at 
                 Rho GDP dissociation inhibitor (GDI) beta 
                 ARHGDIB 
                 397 
                 1 
                 12p12.3 
               
               
                 1116 
                 0.02 
                 1.49 
                 221841_s_at 
                 Kruppel-like factor 4 (gut) 
                 KLF4 
                 9314 
                 1 
                 9q31 
               
               
                 1032 
                 0.02 
                 1.49 
                 202986_at 
                 aryl-hydrocarbon receptor nuclear translocator            
                 ARNT2 
                 9915 
                 1 
                 15q24 
               
               
                 1630 
                 0.03 
                 1.49 
                 1405_i_at 
                 chemokine (C-C motif) ligand 5 
                 CCL5 
                 6352 
                 1 
                 17q11.2-q12 
               
               
                 862 
                 0.02 
                 1.50 
                 205645_at 
                 RALBP1 associated Eps domain containing 2 
                 REPS2 
                 9185 
                 1 
                 Xp22.2-p22.13 
               
               
                 1231 
                 0.02 
                 1.50 
                 217966_s_at 
                 chromosome 1 open reading frame 24 
                 C1orf24 
                 116496 
                 1 
                 1q25 
               
               
                 1549 
                 0.03 
                 1.51 
                 210372_s_at 
                 tumor protein D52-like 1 
                 TPD52L1 
                 7164 
                 1 
                 6q22-q23 
               
               
                 1456 
                 0.03 
                 1.53 
                 202376_at 
                 serpin peptidase inhibitor, clade A (alpha-1 antip           
                 SERPINA3 
                 12 
                 1 
                 14q32.1 
               
               
                 821 
                 0.01 
                 1.53 
                 205278_at 
                 glutamate decarboxylase 1 (brain, 67 kDa) 
                 GAD1 
                 2571 
                 1 
                 2q31 
               
               
                 59 
                 0.0006 
                 1.54 
                 208502_s_at 
                 paired-like homeodomain transcription factor 1 
                 PITX1 
                 5307 
                 1 
                 5q31 
               
               
                 321 
                 0.0044 
                 1.54 
                 200824_at 
                 glutathione S-transferase pi 
                 GSTP1 
                 2950 
                 1 
                 11q13 
               
               
                 342 
                 0.0047 
                 1.55 
                 212325_at 
                 KIAA1102 protein 
                 KIAA1102 
                 22998 
                 1 
                 4p13 
               
               
                 126 
                 0.0015 
                 1.55 
                 208998_at 
                 uncoupling protein 2 (mitochondrial, proton carrie           
                 UCP2 
                 7351 
                 1 
                 11q13 
               
               
                 1358 
                 0.03 
                 1.56 
                 217967_s_at 
                 chromosome 1 open reading frame 24 
                 C1orf24 
                 116496 
                 1 
                 1q25 
               
               
                 817 
                 0.01 
                 1.56 
                 203786_s_at 
                 tumor protein D52-like 1 
                 TPD52L1 
                 7164 
                 1 
                 6q22-q23 
               
               
                 776 
                 0.01 
                 1.57 
                 205990_s_at 
                 wingless-type MMTV integration site family, mem           
                 WNT5A 
                 7474 
                 1 
                 3p21-p14 
               
               
                 1462 
                 0.03 
                 1.57 
                 205471_s_at 
                 dachshund homolog 1 ( Drosophila ) 
                 DACH1 
                 1602 
                 1 
                 13q22 
               
               
                 1748 
                 0.04 
                 1.57 
                 203354_s_at 
                 pleckstrin and Sec7 domain containing 3 
                 PSD3 
                 23362 
                 1 
                 8pter-p23.3 
               
               
                 967 
                 0.02 
                 1.58 
                 202687_s_at 
                 tumor necrosis factor (ligand) superfamily, memb           
                 TNFSF10 
                 8743 
                 1 
                 3q26 
               
               
                 1328 
                 0.03 
                 1.59 
                 218613_at 
                 pleckstrin and Sec7 domain containing 3 
                 PSD3 
                 23362 
                 1 
                 8pter-p23.3 
               
               
                 372 
                 0.01 
                 1.60 
                 204972_at 
                 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 
                 OAS2 
                 4939 
                 1 
                 12q24.2 
               
               
                 144 
                 0.0017 
                 1.62 
                 204984_at 
                 glypican 4 
                 GPC4 
                 2239 
                 1 
                 Xq26.1 
               
               
                 291 
                 0.0039 
                 1.62 
                 202688_at 
                 tumor necrosis factor (ligand) superfamily, memb           
                 TNFSF10 
                 8743 
                 1 
                 3q26 
               
               
                 1475 
                 0.03 
                 1.62 
                 214774_x_at 
                 trinucleotide repeat containing 9 
                 TNRC9 
                 27324 
                 1 
                 16q12.1 
               
               
                 85 
                 0.0010 
                 1.63 
                 221666_s_at 
                 PYD and CARD domain containing 
                 PYCARD 
                 29108 
                 1 
                 16p12-p11.2 
               
               
                 530 
                 0.01 
                 1.63 
                 203649_s_at 
                 phospholipase A2, group IIA (platelets, synovial            
                 PLA2G2A 
                 5320 
                 1 
                 1p35 
               
               
                 46 
                 0.0004 
                 1.67 
                 211828_s_at 
                 TRAF2 and NCK interacting kinase 
                 TNIK 
                 23043 
                 1 
                 3q26.2-q26.31 
               
               
                 151 
                 0.0018 
                 1.70 
                 212327_at 
                 KIAA1102 protein 
                 KIAA1102 
                 22998 
                 1 
                 4p13 
               
               
                 86 
                 0.0011 
                 1.70 
                 204070_at 
                 retinoic acid receptor responder (tazarotene indu           
                 RARRES3 
                 5920 
                 1 
                 11q23 
               
               
                 1656 
                 0.04 
                 1.70 
                 220177_s_at 
                 transmembrane protease, serine 3 
                 TMPRSS3 
                 64699 
                 1 
                 21q22.3 
               
               
                 1538 
                 0.03 
                 1.71 
                 214440_at 
                 N-acetyltransferase 1 (arylamine N-acetyltransfe           
                 NAT1 
                 9 
                 1 
                 8p23.1-p21.3 
               
               
                 167 
                 0.0021 
                 1.71 
                 212328_at 
                 KIAA1102 protein 
                 KIAA1102 
                 22998 
                 1 
                 4p13 
               
               
                 1514 
                 0.03 
                 1.72 
                 203355_s_at 
                 pleckstrin and Sec7 domain containing 3 
                 PSD3 
                 23362 
                 1 
                 8pter-p23.3 
               
               
                 736 
                 0.01 
                 1.73 
                 201860_s_at 
                 plasminogen activator, tissue 
                 PLAT 
                 5327 
                 1 
                 8p12 
               
               
                 265 
                 0.0035 
                 1.74 
                 219630_at 
                 PDZK1 interacting protein 1 
                 PDZK1IP1 
                 10158 
                 1 
                 1p33 
               
               
                 1469 
                 0.03 
                 1.75 
                 209016_s_at 
                 keratin 7 
                 KRT7 
                 3855 
                 1 
                 12q12-q13 
               
               
                 391 
                 0.01 
                 1.76 
                 204364_s_at 
                 chromosome 2 open reading frame 23 
                 C2orf23 
                 65055 
                 1 
                 2p11.2 
               
               
                 106 
                 0.0013 
                 1.80 
                 219850_s_at 
                 ets homologous factor 
                 EHF 
                 26298 
                 1 
                 11p12 
               
               
                 28 
                 0.0003 
                 1.82 
                 217771_at 
                 golgi phosphoprotein 2 
                 GOLPH2 
                 51280 
                 1 
                 9q21.33 
               
               
                 179 
                 0.0023 
                 1.84 
                 214428_x_at 
                 complement component 4A /// complement compo           
                 C4A /// 
                 720 
                 1 
                 6p21.3 
               
               
                   
                   
                   
                   
                   
                 C4B 
               
               
                 172 
                 0.0021 
                 1.84 
                 213693_s_at 
                 mucin 1, transmembrane 
                 MUC1 
                 4582 
                 1 
                 1q21 
               
               
                 260 
                 0.0034 
                 1.90 
                 207847_s_at 
                 mucin 1, transmembrane 
                 MUC1 
                 4582 
                 1 
                 1q21 
               
               
                 193 
                 0.0025 
                 1.92 
                 208451_s_at 
                 complement component 4A /// complement compo           
                 C4A /// 
                 721 
                 1 
                 6p21.3 
               
               
                   
                   
                   
                   
                   
                 C4B 
               
               
                 5 
                 0.0000 
                 1.96 
                 206994_at 
                 cystatin S 
                 CST4 
                 1472 
                 1 
                 20p11.21 
               
               
                 244 
                 0.0032 
                 1.97 
                 219759_at 
                 leukocyte-derived arginine aminopeptidase 
                 LRAP 
                 64167 
                 1 
                 5q15 
               
               
                 392 
                 0.01 
                 1.98 
                 202357_s_at 
                 B-factor, properdin 
                 BF 
                 629 
                 1 
                 6p21.3 
               
               
                 117 
                 0.0014 
                 2.01 
                 209706_at 
                 NK3 transcription factor related, locus 1 ( Drosoph             
                 NKX3-1 
                 4824 
                 1 
                 8p21 
               
               
                 328 
                 0.0045 
                 2.12 
                 220414_at 
                 calmodulin-like 5 
                 CALML5 
                 51806 
                 1 
                 10p15.1 
               
               
                 1343 
                 0.03 
                 2.15 
                 206204_at 
                 growth factor receptor-bound protein 14 
                 GRB14 
                 2888 
                 1 
                 2q22-q24 
               
               
                 614 
                 0.01 
                 2.16 
                 201884_at 
                 carcinoembryonic antigen-related cell adhesion r           
                 CEACAM5 
                 1048 
                 1 
                 19q13.1-q13.2 
               
               
                 476 
                 0.01 
                 2.23 
                 204607_at 
                 3-hydroxy-3-methylglutaryl-Coenzyme A syntha           
                 HMGCS2 
                 3158 
                 1 
                 1p13-p12 
               
               
                 541 
                 0.01 
                 2.34 
                 211657_at 
                 carcinoembryonic antigen-related cell adhesion r           
                 CEACAM6 
                 4680 
                 1 
                 19q13.2 
               
               
                 911 
                 0.02 
                 2.34 
                 203757_s_at 
                 carcinoembryonic antigen-related cell adhesion r           
                 CEACAM6 
                 4680 
                 1 
                 19q13.2 
               
               
                 258 
                 0.0034 
                 3.23 
                 202018_s_at 
                 lactotransferrin 
                 LTF 
                 4057 
                 1 
                 3p21.31 
               
               
                 37 
                 0.0003 
                 4.47 
                 206799_at 
                 secretoglobin, family 1D, member 2 
                 SCGB1D2 
                 10647 
                 1 
                 11q13 
               
               
                 6 
                 0.0001 
                 5.19 
                 206378_at 
                 secretoglobin, family 2A, member 2 
                 SCGB2A2 
                 4250 
                 1 
                 11q13 
               
               
                   
               
               
                             indicates data missing or illegible when filed 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Most preferred genes associated with PIK3CA mutation 
               
             
          
           
               
                 Probe Set ID  
                 Gene Symbol 
                 Gene Title 
                 Entrez Gene ID  
                 Cytoband 
               
               
                   
               
             
          
           
               
                 201288_at 
                 ARHGDIB 
                 Rho GDP dissociation inhibitor (GDI) beta 
                 397 
                 12p12.3 
               
               
                 214553_s_at 
                 ARPP-19 
                 cyclic AMP phosphoprotein, 19 kD 
                 10776 
                 15q21.2 
               
               
                 221586_s_at 
                 E2F5 
                 E2F transcription factor 5, p130-binding 
                 1875 
                 8q21.2 
               
               
                 217787_s_at 
                 GALNT2 
                 UDP-N-acetyl-alpha-D-galactosamine:polypeptide  
                 2590 
                 1q41-q42 
               
               
                   
                   
                 N-acet           
                   
                   
               
               
                 217771_at 
                 GOLM1 
                 golgi membrane protein 1 
                 51280 
                 9q21.33 
               
               
                 203565_s_at 
                 MNAT1 
                 menage a trois homolog 1, cyclin H assembly factor (Xen           
                 4331 
                 14q23 
               
               
                 202431_s_at 
                 MYC 
                 v-myc myelocytomatosis viral oncogene homolog (avian) 
                 4609 
                 8q24.21 
               
               
                 212377_s_at 
                 NOTCH2 
                 Notch homolog 2 ( Drosophila ) 
                 4853 
                 1p13-p11 
               
               
                 211212_s_at 
                 ORC5L 
                 origin recognition complex, subunit 5-like (yeast) 
                 5001 
                 7q22.1 
               
               
                 204992_s_at 
                 PFN2 
                 profilin 2 
                 5217 
                 3q25.1-q25.2 
               
               
                 202743_at 
                 PIK3R3 
                 phosphoinositide-3-kinase, regulatory subunit 3 (gamma) 
                 8503 
                 1p34.1 
               
               
                 206378_at 
                 SCGB2A2 
                 secretoglobin, family 2A, member 2 
                 4250 
                 11q13 
               
               
                 203128_at 
                 SPTLC2 
                 serine palmitoyltransferase, long chain base subunit 2 
                 9517 
                 14q24.3-q31 
               
               
                 211828_s_at 
                 TNIK 
                 TRAF2 and NCK interacting kinase 
                 23043 
                 3q26.2-q26.31 
               
               
                   
               
               
                             indicates data missing or illegible when filed