Overexpression of Prostate-Specific TMPRSS2(exon 0)-ERG Fusion Transcripts Corresponds with Favorable Prognosis of Prostate Cancer

Purpose: To gain insight in the mechanism and clinical relevance of TMPRSS2-ERG expression in prostate cancer, we determined the specific characteristics of fusion transcripts starting at TMPRSS2 exon 1 and at a more upstream and less characterized exon 0. Experimental Design: We used quantitative PCR analysis to investigate expression of wild-type TMPRSS2(exon 0) and TMPRSS2(exon 1) and of ERG fusion transcripts. Expression was tested in normal tissue samples, in prostate cancer cell lines and xenografts, and in fresh-frozen clinical prostate cancer samples (primary tumors and recurrences). Expression in clinical samples was correlated with disease progression. Results: TMPRSS2(exon 0) and TMPRSS2(exon 1) transcripts were similarly androgen regulated in prostate cancer cell lines, but the expression levels of TMPRSS2(exon 1)were much higher. Comparison of expression in different tissues showed TMPRSS2(exon 0) expression to be much more prostate specific. In androgen receptor-positive prostate cancer xenografts, TMPRSS2(exon 1) transcripts were expressed at similar levels, but TMPRSS2(exon 0)transcripts were expressed at very variable levels. The same phenomenon was observed for TMPRSS2-ERG fusion transcripts. In clinical prostate cancers, the expression of TMPRSS2(exon 0)-ERG was even more variable. Expression of TMPRSS2 (exon 0)-ERG transcripts was detected in 55% (24 of 44) of gene fusion-positive primary tumors but only in 15% (4 of 27) of gene fusion-positive recurrences and at much lower levels. Furthermore, in primary tumors, expression of TMPRSS2(exon 0)-ERG transcripts was an independent predictor of biochemical progression-free survival. Conclusion: The expression of TMPRSS2(exon 0)-ERG fusion transcripts in prostate cancer is associated with a less-aggressive biological behavior. (Clin Cancer Res 2009; 15(20):6398-403)