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

Abstract

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. 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. 3 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). 4 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)-...

Cysteine-rich secretory protein 3 overexpression is linked to a subset of PTEN-deleted ERG fusion-positive prostate cancers with early biochemical recurrence

“…Activation of ERG expression, mostly caused by TMPRSS2:ERG gene fusion, results in aberrant activation of different signaling cascades including upregulation of several metabolic enzymes, as well as extracellular/ transmembrane proteins involved in cell adhesion, matrix remodeling, and signal transduction. 13,[24][25][26] Our study identifies CRISP3 as another extracellular protein, which is strongly upregulated in ERG fusionpositive cancers. The functional role of CRISP3 in prostate cancer development and/or progression is unclear.…”

ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer

“…8,[19][20][21][22][23] This variability might be due to differences in study cohorts, clinical end points and methodologies for detecting gene fusion. For example, RT-PCR-detected TMPRSS2-ERG fusion was found in more than 70% of patients surgically treated by radical prostatectomy for prostate cancer.…”

ETS fusion genes in prostate cancer

“…As mentioned earlier, ERG is the most frequently overexpressed ETS gene in prostate cancer. ERG overexpression is found in both early-and late-stage prostate cancer (CRPC) (Tomlins et al 2005, Soller et al 2006, Hermans et al 2009 (Petrovics et al 2005). Later that year, it was discovered that the mechanism underlying this overexpression was the recurrent genomic rearrangement between the first exon(s) of TMPRSS2 and the ERG oncogenes ( Fig.…”

“…TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate (Hermans et al 2009). TMPRSS2 is located on chromosomal band 21q22.…”