Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels |
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Authors: | Parikh Hemang Wang Zhaoming Pettigrew Kerry A Jia Jinping Daugherty Sarah Yeager Meredith Jacobs Kevin B Hutchinson Amy Burdett Laura Cullen Michael Qi Liqun Boland Joseph Collins Irene Albert Thomas J Vatten Lars J Hveem Kristian Njølstad Inger Cancel-Tassin Geraldine Cussenot Olivier Valeri Antoine Virtamo Jarmo Thun Michael J Feigelson Heather Spencer Diver W Ryan Chatterjee Nilanjan Thomas Gilles Albanes Demetrius Chanock Stephen J Hunter David J Hoover Robert Hayes Richard B Berndt Sonja I Sampson Joshua Amundadottir Laufey |
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Affiliation: | 1. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20877, USA 2. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA 3. Core Genotyping Facility, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, 21702, USA 4. Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, BT9 7BL, Ireland 5. Roche NimbleGen, Madison, WI, 53711, USA 6. Department of Public Health and General Practice, Norwegian University of Science and Technology, 7489, Trondheim, Norway 7. Department of Community Medicine, Faculty of Health Sciences, University of Troms?, 9037, Troms?, Norway 8. Centre de Recherche pour les Pathologies Prostatiques (CeRePP), H?pital Tenon, Assistance Publique-H?pitaux de Paris, 75020, Paris, France 9. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, 00300, Finland 10. Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30329, USA 11. Synergie-Lyon-Cancer, INSERM U590, Centre Leon Berard, 69373, Lyon Cedex 08, France 12. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA 13. Division of Epidemiology, Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10016, USA 14. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Institutes of Health, 8717 Grovemont Circle, Gaithersburg, MD, 20877, USA
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Abstract: | 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 both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56?kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case?Ccontrol studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P?=?0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P?=?3.41?×?10?4, per-allele trend odds ratio (OR)?=?0.77, 95% CI?=?0.67?C0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage P?=?4.72?×?10?5, per-allele trend OR?=?0.68, 95% CI?=?0.57?C0.82) and not for advanced cases with Gleason score >8 or stage ??III (P?=?0.31, per-allele trend OR?=?1.12, 95% CI?=?0.90?C1.40). 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 43.7% higher in control subjects with no minor alleles (1.61?ng/ml, 95% CI?=?1.49?C1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12?ng/ml, 95% CI?=?0.96?C1.28) (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. |
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