Identification of an aggressive prostate cancer predisposing variant at 11q13

Abstract

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] 5 7.5; 95% confidence interval [CI] 5 1.3-45.5; p 5 0.02). Further analysis with clinicopathological data revealed that the variant is associated with aggressive unselected cases (prostate specific antigen ! 20 lg/L or Gleason grade ! 7), based on both case-control (OR 5 6.0; 95% CI 5 1.3-26.4; p 5 0.03) and case-case analyses (OR 5 6.5; 95% CI 5 1.5-28.4; p 5 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.

Germline EMSY sequence alterations in hereditary breast cancer and ovarian cancer families

“…Interestingly, the aggressive SNP was segregated with breast cancer in a prostate cancer family [28]. However, in the present study, we did not detect the aggressive SNP.…”

“…We previously examined the association of EMSY SNPs with prostate cancer predisposition and identified a rare intronic SNP that increases the risk of aggressive prostate cancer (referred to as aggressive SNP) [28]. Interestingly, the aggressive SNP was segregated with breast cancer in a prostate cancer family [28].…”

“…In addition to breast cancer, EMSY is overexpressed in high-grade ovarian cancer [13, 25, 26] and pancreatic cancer [27]. Previously, we examined the association of EMSY single-nucleotide polymorphisms (SNPs) in relation to prostate cancer predisposition and identified a rare intronic SNP that increases the risk of aggressive prostate cancer [28]. …”

EMSY promoted the growth and migration of ovarian cancer cells

“…These observations suggested the BRCA2-independent function of EMSY. Besides, recent studies have shown that amplification of EMSY was also associated with other cancers such as prostate and pancreatic cancers [14,15].…”

Expression of EMSY, a Novel BRCA2-link Protein, is Associated with Lymph Node Metastasis and Increased Tumor Size in Breast Carcinomas

“…EMSY localizes to the sites of DNA repair following DNA damage and maps to chromosome 11q13.5, 100 kb centromeric to the GARP gene, a locus that is known to be involved in a number of cancers including breast, ovarian and prostate cancers (Nurminen et al, 2011). Recently Nurminen et al showed that 11q13.5 contributes to prostate cancer predisposition with complex genetic structure and is associated with prostate cancer death (Nurminen et al, 2013).…”