Association of Prostate Cancer Risk Variants with TMPRSS2:ERG Status: Evidence for Distinct Molecular Subtypes

Background: Numerous genetic variants have been confirmed as prostate cancer risk factors. These variants may confer susceptibility to the development of specific molecular alterations during tumor initiation and progression. The TMPRSS2:ERG gene fusion occurs in roughly 50% of prostate cancers. Genetic risk variants may influence the development of this fusion. We sought to determine whether prostate cancer risk variants are differentially associated with TMPRSS2: ERG fusion-positive and negative cancer. Methods: In the Health Professionals Follow-up Study and Physicians' Health Study Tumor Cohort, we evaluated the associations of 39 prostate cancer risk SNPs with TMPRSS2: ERG fusion status, measured by ERG protein expression. Logistic regression was performed to generate OR and 95% confidence intervals. The primary outcome was ERG(-) (n = 227) versus ERG(-) ( n = 260) prostate cancer. A secondary outcome was ERG(-) or ERG(-) cancer versus controls without cancer. Results: Six of 39 SNPs were significantly associated (P < 0.05) with ERG(-) versus ERG(-) disease. Three SNPs were exclusively associated with the risk of ERG(-), one with risk of ERG(-), and two with associations trending in opposite directions for ERG(-) and ERG(-). Only two significant SNPs would be expected by chance. Conclusions: Prostate cancer genetic risk variants are differentially associated with the development of ERG(-) and ERG(-) prostate cancer. Impact: Our findings suggest the molecular process of prostate carcinogenesis may be distinct for men with different underlying genetic predisposition. When examining risk factors for prostate cancer, the integration of molecular subtypes may enhance understanding of the etiology of this disease. (C) 2016 AACR.