Abstract 3513: Genome-wide scan for novel prostate cancer susceptibility loci with clinical consequence utilizing increased genetic drift of the Finnish population

Abstract

Abstract Background: Prostate cancer (PC) is the second most common cancer in men worldwide with a rising prevalence. However, only limited number of clinically actionable variants are known. The objective of this study is to identify novel PC susceptibility loci with potential clinical relevance utilizing the increased genetic drift and reduced selective pressure of the recently bottlenecked powerful resource of the Finnish population. Methods: We meta-analysed >185.000 germline single nucleotide polymorphisms (SNPs) in 2738 PC cases and 2401 controls of Finnish origin in the Collaborative Oncological Gene-Environment Study (COGS) using Illumina iSelect custom SNP genotyping platform. Results: Altogether 160 variants remain significant on GWAS level (p<5 × 10−8) in 18 different gene regions. Out of the 160 identified PC susceptibility hits 78 (49%) are novel variants not reported earlier in association with PC. PC associated signals are in close proximity to one another forming genetic hot-spots on chromosomes 8, 7, 11, 17 and 19. The strength of association varies for 101 PC risk variants (OR 1.24-1.86) and 59 protective SNPs (OR 0.59-0.80). The strongest risk gene is CASC8 (OR=1.86; p=1.214 × 10−11). The most significant signals were found at the 8p21.2 chromosomal region (p<7.6 × 10−16). Functional annotation identified a missense coding SNP at KLK3 gene to be a candidate causal variant. We showed evidence for association both with early-onset PC (OR 1.73; P=0.02), high serum PSA level at diagnosis (OR 1.36; P=0.024) and with aggressive PC (Gleason score ≥8; OR 1.44; P=0.02) at 17q21. Conclusion: The results facilitate risk stratification for screening, clinical studies, treatment choices and functional research of PC Citation Format: Csilla Sipeky, Teuvo L. Tammela, Anssi Auvinen, Johanna Schleutker. Genome-wide scan for novel prostate cancer susceptibility loci with clinical consequence utilizing increased genetic drift of the Finnish population [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3513.