TMPRSS2-ERG transcript heterogeneity in human prostate cancers: Insights from a prospective prostate biopsy series

2175 Introduction: The discovery that the majority of human prostate cancers contain a recurrent genomic rearrangement involving one of the ETS family oncogenes has introduced an important new class of biomarkers for this disease. Most commonly, a chromosome 21q22.2-3 rearrangement places ERG expression under the control of a prostate-specific, androgen regulated TMPRSS2 promoter. TMPRSS2-ERG fusions show considerable variability, and it9s been proposed that specific TMPRSS2-ERG transcript structure(s) may be directly associated with prostate cancer aggressiveness. We have analyzed TMPRSS2-ERG at the mRNA and genomic levels in prostate cancer patients from a prospectively collected needle biopsy cohort. Using high quality RNA samples, we found that only a subset of TMPRSS2-ERG positive cases produce fusion transcripts that are long enough to contain the complete coding sequence of the truncated ERG oncogene. In this study, our objective was to assess the relative contribution of these potentially “full length” TMPRSS2-ERG transcripts to this pivotal molecular event in prostate cancer pathobiology. Experimental methods: Prostate biopsy patients were enrolled in a protocol in which tissue print micropeel “touch preps” were collected from each biopsy core (12 cores/patient). Tissue cores were processed as usual for pathology; after a histological diagnosis had been established, additional sections were obtained for FISH analysis of chromosome 21q22-3 rearrangements. Tissue prints were snap frozen upon collection; purified RNA and DNA fractions were prepared from each print for molecular analysis. Rt-PCR and direct sequencing were used to determine the detailed molecular characteristics of specific TMPRSS2-ERG transcripts. Results: In our biopsy series, approx 50% of the prostate cancer patients who were positive for TMPRSS2-ERG expressed relatively long forms of the fusion transcript (1-2 Kb from TMPRSS2 exon 1 to 3’UTR of ERG). Comparable wild type ERG transcripts containing the full coding sequence of the oncogene are approx 1.4 Kb. Interestingly, in the subset of patients positive for 1-2 Kb TMPRSS2-ERG transcripts, approx 80% showed Gleason 7 or higher grade cancer on biopsy, suggesting a predisposition for more aggressive tumors among patients whose prostate cancer(s) express longer forms of this fusion mRNA. Conclusions: The characteristics of the TMPRSS2-ERG fusions found at biopsy may provide insight into the molecular etiology of a patient’s tumor(s). Moreover, our data suggest that patients with TMPRSS2-ERG transcripts that are long enough to contain all of the coding sequence of the truncated ERG oncogene are more likely to have higher Gleason score tumors, providing a potential molecular marker for more aggressive disease. (supported by NIH/NCI funding through the IMAT and EDRN programs and by a research grant from New England Baptist Hospital)