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

Burcu F Darst 1 Peggy Wan 1 Xin Sheng 1 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 2, 3 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 4 Marie-Elise Parent Florence Menegaux 5 Geraldine Cancel-Tassin Adam S Kibel Eric A Klein Phyllis J Goodman Bettina F Drake Jennifer J Hu Peter E Clark Pascal Blanchet 4, 6 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 1 Christopher A Haiman 1, *
Abstract : 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.
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Burcu F Darst, Peggy Wan, Xin Sheng, Jeannette T Bensen, Sue A Ingles, et al.. A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry. European Urology, Elsevier, 2020, 78 (3), pp.316-320. ⟨10.1016/j.eururo.2020.04.060⟩. ⟨hal-02860251⟩

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