Abstract 2778: Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels
Authors: Hemang M. Parikh, Zhaoming Wang, Kerry Pettigrew, Jinping Jia, Sarah Daugherty, Meredith Yeager, Kevin Jacobs, Amy Hutchinson, Laura Burdett, Michael Cullen, Liqun Qi, Joseph Boland, Irene Collins, Thomas Albert, Lars Vatten, Kristian Hveem, Inger Njølstad, Geraldine Cancel-Tassin, Olivier Cussenot, Antoine Valeri, Jarmo Virtamo, Michael Thun, Heather Spencer Feigelson, W. Ryan Diver, Nilanjan Chatterjee, Gilles Thomas, Demetrius Albanes, Stephen Chanock, David Hunter, Robert Hoover, Richard Hayes, Sonja Berndt, Joshua Sampson, Laufey Amundadottir
Journal: Cancer Research (2011)

Abstract Prostate cancer is the most commonly diagnosed non-cutaneous cancer in men in the United States with over 200,000 new cases and 30,000 deaths estimated in 2010. Measurements of serum prostate specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with serum PSA levels. In genome-wide association studies (GWAS) of prostate cancer, KLK3 variants have been suggested to be prostate cancer risk factors. Based on a resequence analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, that characterized common germline variations in the region, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five cohort and case-control studies. The cohort studies are: the Prostate, Lung, Colon and Ovarian (PLCO) Cancer Screening Trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), the American Cancer Society Prevention Study II Nutrition Cohort (CPS-II) and the Cohort of Norway (CONOR). The case-control study is the French Prostate Case-Control Study (CeRePP) which is a hospital based case-control study. This study has &amp;gt; 80% power to detect an association with an odds ratio of 1.25 (assuming a MAF of 0.05, a prevalence of prostate cancer = 1.5067% and alpha = 0.05). We did not observe a strong association for KLK3 variants, previously reported to confer risk for prostate cancer (rs2735839; P = 0.20). However, three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) demonstrated an association with prostate cancer (P = 3.41×10−4, per-allele odds ratio (OR) = 0.77, 95% CI = 0.67-0.89). In particular, the signal is apparent in nonaggressive prostate cancer cases with Gleason score &amp;lt; 7 and disease stage &amp;lt; III (P = 2.62×10−5, per-allele trend OR = 0.67, 95% CI = 0.56-0.81) but not in advanced cases with Gleason score &amp;gt; 8 or stage ≥ III (P = 0.31, per-allele OR = 1.12, 95% CI = 0.90-1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were lower in control subjects with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96-1.28) as compared to those with no minor alleles (1.61 ng/ml, 95% CI = 1.49-1.72) (P = 9.70×10−5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy. It is possible that the KLK3 locus also contributes to prostate cancer risk, but additional studies will be needed to dissect the contribution of KLK3 to PSA and prostate risk separately. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2778. doi:10.1158/1538-7445.AM2011-2778