Title

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Authors

Fredrick R. Schumacher, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. frs2@case.edu.
Ali Amin Al Olama, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK. aa461@medschl.cam.ac.uk.
Sonja I. Berndt, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
Sara Benlloch, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
Mahbubl Ahmed, Institute of Cancer Research, London, UK.
Edward J. Saunders, Institute of Cancer Research, London, UK.
Tokhir Dadaev, Institute of Cancer Research, London, UK.
Daniel Leongamornlert, Institute of Cancer Research, London, UK.
Ezequiel Anokian, Institute of Cancer Research, London, UK.
Clara Cieza-Borrella, Institute of Cancer Research, London, UK.
Chee Goh, Institute of Cancer Research, London, UK.
Mark N. Brook, Institute of Cancer Research, London, UK.
Xin Sheng, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Laura Fachal, Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain.
Joe Dennis, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
Jonathan Tyrer, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
Kenneth Muir, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, UK.
Artitaya Lophatananon, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, UK.
Victoria L. Stevens, Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
Susan M. Gapstur, Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
Brian D. Carter, Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
Catherine M. Tangen, SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Phyllis J. Goodman, SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Ian M. Thompson, CHRISTUS Santa Rosa Hospital-Medical Center, San Antonio, TX, USA.
Jyotsna Batra, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
Suzanne Chambers, Menzies Health Institute of Queensland, Griffith University, Nathan, Queensland, Australia.
Leire Moya, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
Judith Clements, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
Lisa Horvath, Chris O'Brien Lifehouse (COBLH), Camperdown, New South Wales, Australia.
Wayne Tilley, Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.
Gail P. Risbridger, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Program, Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia.
Henrik Gronberg, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Markus Aly, Department of Urology, Karolinska University Hospital, Stockholm, Sweden.

Document Type

Article

Publication Date

7-1-2018

Abstract

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa.

Publication Source (Journal or Book title)

Nature genetics

First Page

928

Last Page

936

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