A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry
Darst BF, Wan P, Sheng X, Bensen JT, Ingles SA, Rybicki BA, Nemesure B, John EM, Fowke JH, Stevens VL, Berndt SI, Huff CD, Strom SS, Park JY, Zheng W, Ostrander EA, Walsh PC, Srivastava S, Carpten J, Sellers TA, Yamoah K, Murphy AB, Sanderson M, Crawford DC, Gapstur SM, Bush WS, Aldrich MC, Cussenot O, Yeager M, Petrovics G, Cullen J, Neslund-Dudas C, Kittles RA, Xu J, Stern MC, Kote-Jarai Z, Govindasami K, Chokkalingam AP, Multigner L, Parent ME, Menegaux F, Cancel-Tassin G, Kibel AS, Klein EA, Goodman PJ, Drake BF, Hu JJ, Clark PE, Blanchet P, Casey G, Hennis AJM, Lubwama A, Thompson IM, Jr., Leach R, Gundell SM, Pooler L, Xia L, Mohler JL, Fontham ETH, Smith GJ, Taylor JA, Eeles RA, Brureau L, Chanock SJ, Watya S, Stanford JL, Mandal D, Isaacs WB, Cooney K, Blot WJ, Conti DV, and Haiman CA. A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry. Eur Urol 2020.
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.
ePub ahead of print