Identification of an aggressive prostate cancer predisposing variant at 11q13

Prostate cancer is the most frequently diagnosed cancer in men; however, the genetic basis of susceptibility remains elusive. The EMSY gene is located in the prostate cancer linked chromosome region at 11q13.5. The aim of this study was to screen EMSY for sequence variants and to evaluate its association with the risk of prostate cancer. We performed a Finnish population-based case-control study with 923 controls, 184 familial prostate cancer cases and 2,301 unselected prostate cancer cases. Variants were screened using sequencing and validated using the TaqMan assay and High Resolution Melting analysis. A total of 27 sequence variants were found, and 17 of them were novel. A rare intronic variant, IVS6-43A>G (minor allele frequency of 0.004), increased the prostate cancer risk in familial cases (odds ratio [OR] = 7.5; 95% confidence interval [CI] = 1.3-45.5; p = 0.02). Further analysis with clinicopathological data revealed that the variant is associated with aggressive unselected cases (prostate specific antigen ≥ 20 μg/L or Gleason grade ≥ 7), based on both case-control (OR = 6.0; 95% CI = 1.3-26.4; p = 0.03) and case-case analyses (OR = 6.5; 95% CI = 1.5-28.4; p = 0.002). In addition, all variant-positive familial cases had aggressive cancer. Our results indicate that the intronic variant IVS6-43A>G increases the familial and unselected prostate cancer risk in a Finnish population and contributes to the aggressive progression of the disease in a high-penetrance manner. The potential role of the variant as a predictive genetic marker for aggressive prostate cancer should be further evaluated.