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A germline variant at 8q24 contributes to familial clustering of prostate cancer in men of african ancestry

  • 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 Jr,
  • 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

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.