A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

European urology. 2020 May 11 [Epub ahead of print]

Burcu F Darst, Peggy Wan, Xin Sheng, Jeannette T Bensen, Sue A Ingles, Benjamin A Rybicki, Barbara Nemesure, Esther M John, Jay H Fowke, Victoria L Stevens, Sonja I Berndt, Chad D Huff, Sara S Strom, Jong Y Park, Wei Zheng, Elaine A Ostrander, Patrick C Walsh, Shiv Srivastava, John Carpten, Thomas A Sellers, Kosj Yamoah, Adam B Murphy, Maureen Sanderson, Dana C Crawford, Susan M Gapstur, William S Bush, Melinda C Aldrich, Olivier Cussenot, Meredith Yeager, Gyorgy Petrovics, Jennifer Cullen, Christine Neslund-Dudas, Rick A Kittles, Jianfeng Xu, Mariana C Stern, Zsofia Kote-Jarai, Koveela Govindasami, Anand P Chokkalingam, Luc Multigner, Marie-Elise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Adam S Kibel, Eric A Klein, Phyllis J Goodman, Bettina F Drake, Jennifer J Hu, Peter E Clark, Pascal Blanchet, Graham Casey, Anselm J M Hennis, Alexander Lubwama, Ian M Thompson, Robin Leach, Susan M Gundell, Loreall Pooler, Lucy Xia, James L Mohler, Elizabeth T H Fontham, Gary J Smith, Jack A Taylor, Rosalind A Eeles, Laurent Brureau, Stephen J Chanock, Stephen Watya, Janet L Stanford, Diptasri Mandal, William B Isaacs, Kathleen Cooney, William J Blot, David V Conti, Christopher A Haiman

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA., Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA., Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA., Department of Epidemiology and Population Health and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Division of Epidemiology, Department of Preventive Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA., Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA., Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, MD, USA., Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA., Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA., Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., The James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA., Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Department of Radiation Oncology and Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Urology, Northwestern University, Chicago, IL, USA., Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, USA., Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA., Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA., CeRePP and Sorbonne Universite, GRC n° 5, AP-HP, Tenon Hospital, Paris, France., Department of Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Program for Personalized Cancer Care and Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA., The Institute of Cancer Research, Sutton, London, UK., Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, London, UK., School of Public Health, University of California, Berkeley, Berkeley, CA, USA., Inserm U1085-IRSET, Rennes, France., INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, University of Quebec, Laval, Quebec, Canada., INSERM, Center for Research in Epidemiology and Population Health, Team Cancer-Environment, Université Paris-Saclay, Université Paris-Sud, Villejuif, France., Division of Urology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA; Washington University, St. Louis, MO, USA., Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA., SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, USA., Sylvester Comprehensive Cancer Center and Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA., Vanderbilt University Medical Center, Nashville, TN, USA., Inserm U1085-IRSET, Rennes, France; University Hospital of Pointe-à-Pitre, Guadeloupe, FWI, France; French West Indies University, Pointe-à-Pitre, Guadeloupe, FWI, France., Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA., Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA; Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados., School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda., Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA., School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA., Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA., Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA., The Institute of Cancer Research, Sutton, London, UK; Royal Marsden NHS Foundation Trust, London, UK., School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda; Uro Care, Kampala, Uganda., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA., Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA., Department of Medicine, Duke University of Medicine, Durham, NC, USA., Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. Electronic address: .

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