Discovery of a novel set of prostate cancer-related genes associated with the prognostically important TMPRSS2:ERG fusion gene.

5056 Background: Nam et al (BJC 97:1690, 2007) have recently shown that of 165 patients, the subgroup of patients who expressed the TMPRSS2:ERG fusion gene product, had a significantly higher risk of recurrence (58% at 5 yrs) than did patients who lacked the fusion protein (8% at 5 yrs) and was the single most important prognostic factor. We have used the DASL assay to expression profile 502 cancer-related genes in tumors from 145 patients from this study in order to characterize a set of additional genes that correlate with recurrence and that may shed light on novel therapeutic targets.,Patients were drawn from men who underwent radical prostatectomy as the sole treatment for clinically localized PC between 1998 and 2006; at Sunnybrook Health Science Center (Toronto, ON). Most patients had a Gleason score of 7 and the primary endpoint was biochemical recurrence. Total RNA, previously prepared from frozen PC samples, was used in the DASL assay. Labeled PCR products were hybridized to a Sentrix Universal Array which was imaged using a BeadArray Reader. Data was analyzed using BeadStudio, Significance Analysis of Microarrays, Cluster, and Treeview software.,RT-PCR results previously classified 73 of the 145 samples as TMPRSS2:ERG gene fusion-positive and 72 as fusion-negative. Of the fusion negative only 4 samples (5.5%) showed recurrence as opposed to 28 of the 73 fusion positive samples which showed recurrence (38.4%). DASL signal intensity supports the RT-PCR results showing an average increase in ERG signal intensity of over 3-fold for samples classified as fusion-positive via RT-PCR versus those classified as fusion-negative. Associated with this bifurcation are 8 other positively regulated genes (MSF, ARHGDIB, PDGFA, HDAC1, THPO, EPHB4, CEACAM1, TRAF4) and 15 negatively regulated genes (LAF4, CD44, FGF12, EPO, IGF1, FGFR4, MAF, TGFB3, FLT1, FGF7, KDR, PTEN, PDGFRA, ETV1, IGF2) with a false discovery rate of 3%.,Using the DASL assay on 145 patient samples we have discovered 23 regulated genes that deserve further investigation and may act as therapeutic targets. Four of these genes (CEACAM1, MSF, PDGFA and THPO) are angiogenesis-related and one that is histone acetylase-related suggest immediate therapeutic approaches. No significant financial relationships to disclose.