Retention of Interstitial Genes between <i>TMPRSS2</i> and <i>ERG</i> Is Associated with Low-Risk Prostate Cancer.

Abstract

<i>TMPRSS2-ERG</i> gene fusions occur in over 50% of prostate cancers, but their impact on clinical outcomes is not well understood. Retention of interstitial genes between <i>TMPRSS2</i> and <i>ERG</i> has been reported to influence tumor progression in an animal model. In this study, we analyzed the status of <i>TMPRSS2-ERG</i> fusion genes and interstitial genes in tumors from a large cohort of men treated surgically for prostate cancer, associating alterations with biochemical progression. Through whole-genome mate pair sequencing, we mapped and classified rearrangements driving ETS family gene fusions in 133 cases of very low-, low-, intermediate-, and high-risk prostate cancer from radical prostatectomy specimens. <i>TMPRSS2-ERG</i> gene fusions were observed in 44% of cases, and over 90% of these fusions occurred in <i>ERG</i> exons 3 or 4. <i>ERG</i> fusions retaining interstitial sequences occurred more frequently in very low-risk tumors. These tumors also frequently displayed <i>ERG</i> gene fusions involving alternative 5'-partners to <i>TMPRSS2</i>, specifically <i>SLC45A3</i> and <i>NDRG1</i> and other ETS family genes, which retained interstitial <i>TMPRSS2/ERG</i> sequences. Lastly, tumors displaying <i>TMPRSS2-ERG</i> fusions that retained interstitial genes were less likely to be associated with biochemical recurrence (<i>P</i> = 0.028). Our results point to more favorable clinical outcomes in patients with ETS family fusion-positive prostate cancers, which retain potential tumor-suppressor genes in the interstitial regions between <i>TMPRSS2</i> and <i>ERG</i> Identifying these patients at biopsy might improve patient management, particularly with regard to active surveillance. <i>Cancer Res; 77(22); 6157-67. ©2017 AACR</i>.