Gene Expression Profile Algorithm and Test for Determining Prognosis of Prostate Cancer

Abstract

The present invention provides algorithm-based molecular assays that involve measurement of expression levels of genes, or their co-expressed genes, from a biological sample obtained from a prostate cancer patient. The genes may be grouped into functional gene subsets for calculating a quantitative score useful to predict a likelihood of a clinical outcome for a prostate cancer patient.

What is claimed is: 
     
         1 . A method of predicting a likelihood of a clinical outcome for a patient with prostate cancer, comprising:
 determining a level of one or more RNA transcripts, or an expression product thereof, in a biological sample containing cancer cells obtained from said patient, wherein the one or more RNA transcripts, or an expression product thereof, is selected from BIN1, IGF1, C7, GSN, DES, TGFB1I1, TPM2, VCL, FLNC, ITGA7, COL6A1, PPP1R12A, GSTM1, GSTM2, PAGE4, PPAP2B, SRD5A2, PRKCA, IGFBP6, GPM6B, OLFML3, HLF, CYP3A5, KRT15, KRT5, LAMB3, SDC1, DUSP1, EGFR1, FOS, JUN, EGR3, GADD45B, ZFP36, FAM13C, KLK2, ASPN, SFRP4, BGN, THBS2, INHBA, COL1A1, COL3A1, COL1A2, SPARC, COL8A1, COL4A1, FN1, FAP, COL5A2, CDC20, TPX2, UBE2T, MYBL2, and CDKN2C;   assigning the one or more RNA transcripts, or an expression product thereof, to one or more gene groups selected from a cellular organization gene group, basal epithelia gene group, a stress response gene group, an androgen gene group, a stromal response gene group, and a proliferation gene group;   calculating a quantitative score for the patient by weighting the level of one or more RNA transcripts, or an expression product thereof, by their contribution to a clinical outcome; and   predicting a likelihood of a clinical outcome for the patient based on the quantitative score.   
     
     
         2 . The method of  claim 1 , further comprising:
 determining a level of at least one RNA transcript, or an expression product thereof, in the biological sample, wherein the at least one RNA transcript, or an expression product thereof, is selected from STAT5B, NFAT5, AZGP1, ANPEP, IGFBP2, SLC22A3, ERG, AR, SRD5A2, GSTM1, and GSTM2; and   weighting the level of the at least one RNA transcript, or an expression product thereof, by its contribution to the clinical outcome to calculate the quantitative score.   
     
     
         3 . The method of  claim 1 , wherein an increase in the quantitative score correlates with an increased likelihood of a negative clinical outcome. 
     
     
         4 . The method of  claim 1 , wherein the clinical outcome is upgrading of prostate cancer. 
     
     
         5 . The method of  claim 1 , wherein the clinical outcome is upstaging of prostate cancer. 
     
     
         6 . The method of  claim 1 , wherein the clinical outcome is recurrence of prostate cancer. 
     
     
         7 . The method of  claim 1 , wherein the level of at least three RNA transcripts, or their expression products, from the stromal response gene group are determined, and wherein the stromal response gene group comprises ASPN, BGN, COL1A1, SPARC, FN1, COL3A1, COL4A1, INHBA, THBS2, and SFRP4. 
     
     
         8 . The method of  claim 1 , wherein the level of at least one RNA transcript, or its expression product, from the androgen gene group is determined, and wherein the androgen gene group comprises FAM13C, KLK2, AZGP1, and SRD5A2. 
     
     
         9 . The method of  claim 1 , further comprising determining the level of at least three RNA transcripts, or their expression products, from the cellular organization gene group, wherein the cellular organization gene group comprises FLNC, GSN, GSTM2, IGFBP6, PPAP2B, PPP1R12A, BIN1, VCL, IGF1, TPM2, C7, and GSTM1. 
     
     
         10 . The method of  claim 1 , further comprising determining the level of at least one RNA transcript, or its expression product, from the proliferation gene group, wherein the proliferation gene group comprises TPX2, CDC20, and MYBL2. 
     
     
         11 . The method of  claim 1 , wherein the level of any one of the gene combinations shown in Table 4 are determined. 
     
     
         12 . The method of  claim 1 , wherein the quantitative score is calculated based on any one of the algorithms shown in Table 4. 
     
     
         13 . The method of  claim 1 , wherein the RNA transcripts, or their expression products, of BGN, COL1A1, SFRP4, FLNC, GSN, TPM2, FAM13C, and KLK2 are assigned to the following gene groups:
 a) stromal response gene group: BGN, COL1A1, and SFRP4   b) cellular organization gene group: FLNC, GSN, and TPM2 and   c) androgen gene group: FAM13C and KLK2; and   
       wherein the level of the RNA transcripts, or their expression products, of at least one of a)-c) are determined. 
     
     
         14 . A method of predicting a likelihood of a clinical outcome for a patient with prostate cancer, comprising:
 determining a level of one or more RNA transcripts, or an expression product thereof, in a biological sample containing cancer cells obtained from said patient, wherein the one or more RNA transcripts, or an expression product thereof, is selected from BGN, COL1A1, SFRP4, FLNC, GSN, GSTM2, TPM2, AZGP1, KLK2, FAM13C1, SRD5A2, and TPX2,   normalizing the level of the one or more RNA transcripts, or an expression product thereof, to obtain a normalized expression level of the one or more RNA transcripts, or an expression product thereof,   comparing the normalized expression level to gene expression data in reference prostate cancer samples, and   predicting the likelihood of one or more of adverse pathology, non-organ-confined disease, high-grade disease, or high-grade or non-organ-confined disease in the patient based on the normalized expression level of the one or more RNA transcripts, or an expression product thereof,   wherein increased normalized expression levels of BGN, COL1A1, SFRP4, and TPX2 correlate with an increased likelihood of adverse pathology, non-organ-confined disease, high-grade disease, or high-grade or non-organ confined disease, and   wherein increased normalized expression levels of FLNC, GSN, GSTM2, TPM2, AZGP1, KLK2, FAM13C1, and SRD5A2 correlate with a decreased likelihood of adverse pathology, non-organ-confined disease, high-grade disease, or high-grade or non-organ confined disease.   
     
     
         15 . The method of  claim 14 , further comprising assigning the one or more RNA transcripts, or an expression product thereof, to one or more gene groups selected from a cellular organization gene group an androgen gene group, a stromal response gene group, and a proliferation gene group;
 calculating one or more quantitative scores for the patient by weighting the normalized expression level of one or more RNA transcripts, or an expression product thereof, by their contribution to a clinical outcome; and   predicting the likelihood of one or more of adverse pathology, non-organ-confined disease, high-grade disease, or high-grade or non-organ-confined disease for the patient based on the one or more quantitative scores;   wherein the quantitative score is selected from a stromal response group score, cellular organization group score, androgen group score, proliferation group score, and recurrence score;   wherein the stromal response group score comprises the normalized expression levels of BGN, COL1A1, and SFRP4; the cellular organization group score comprises the normalized expression levels of FLNC, GSN, TPM2, and GSTM2; the androgen group score comprises the normalized expression levels of FAM13C, LK2, AZGP1, and SRD5A2; the proliferation group score comprises the normalized expression level of TPX2; and the recurrence score comprises the stromal response group score, cellular organization group score, androgen group score, and proliferation group score; and   wherein an increased stromal response group score, proliferation group score, and recurrence score correlate with an increased likelihood of adverse pathology, non-organ-confined disease, high-grade disease, or high-grade or non-organ confined disease, and an increased cellular organization group score and androgen group score correlate with a decreased likelihood of adverse pathology, non-organ-confined disease, high-grade disease, or high-grade or non-organ confined disease.   
     
     
         16 . The method of  claim 14 , wherein the biological sample is a tissue sample. 
     
     
         17 . The method of  claim 16 , wherein the tissue sample is fixed, paraffin-embedded, or fresh, or frozen. 
     
     
         18 . The method of  claim 14 , wherein the level of one or more RNA transcripts is determined by quantitative RT-PCR. 
     
     
         19 . The method of  claim 14 , further comprising creating a report summarizing the prediction. 
     
     
         20 . The method of  claim 14 , wherein the levels of the RNA transcripts, or expression products thereof, of BGN, COL1A1, SFRP4, FLNC, GSN, GSTM2, TPM2, AZGP1, KLK2, FAM13C1, SRD5A2, and TPX2, are determined.