Imaging, Diagnosis, Prognosis 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 inprostate cancer,wedetermined 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 ofTMPRSS2(exon1)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 phenomenonwas 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) Recently, recurrent fusions of prostate-specific and androgenregulated TMPRSS2 to the ETS genes ERG, ETV1, ETV4, and ETV5 have been reported as the most frequent genetic alterations in clinical prostate cancer (1–7). TMPRSS2-ERG fusion is detected in 40% to 70% of clinical prostate cancers. Fusion of ETV1, ETV4, and ETV5 to TMPRSS2 are much less frequent, but ETV1, ETV4, and ETV5 have multiple fusion partners. Expression of most of these partner genes is prostate specific and androgen regulated (1–5). Some clinical studies have shown TMPRSS2-ERG to be associated with a more aggressive prostate cancer phenotype (8–12). However, other studies did not find an association with outcome in patients treated by radical prostatectomy (13, 14) or even described TMPRSS2-ERG to be correlated with a more favorable outcome (15, 16). TMPRSS2 has more than one first exon. Not only fusion transcripts starting at the well-known TMPRSS2 exon 1 but also transcripts that start from a more upstream and less characterized alternative first exon, here denoted exon 0, have been identified (14). In the present study, we determined the specific characteristics of TMPRSS2 transcripts starting at exons 1 and 0 in benign prostatic tissue and in prostate cancer. Moreover, we investigated clinical prostate cancer samples (primary tumors and recurrences) for expression of TMPRSS2(exon 0)-ERG and TMPRSS2 Authors' Affiliations: Department of Pathology, Josephine Nefkens Institute and Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands Received 5/15/09; revised 7/7/09; accepted 7/20/09; published OnlineFirst 10/13/09. The costs of publication of this articlewere defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). K.G. Hermans and J.L. Boormans contributed equally to this work. Requests for reprints: Jan Trapman, Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Phone: 31107043933; Fax: 31107044762; Email: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1176 3 UCSC Genome Browser (genome.ucsc.edu). 4 K.G. Hermans, unpublished observation. 6398 Clin Cancer Res 2009;15(20) October 15, 2009 www.aacrjournals.org Published Online First on October 13, 2009 as 10.1158/1078-0432.CCR-09-1176 Research. on July 15, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst October 13, 2009; DOI: 10.1158/1078-0432.CCR-09-1176