Abstract
Abstract Germline variation at 8q24 is the strongest risk factor for prostate cancer (PCa) across all racial and ethnic populations. While most 8q24 associations have been observed across populations, rs72725854 [T risk allele frequency ~6%] is only found in men of African ancestry and is the strongest known genome-wide association signal for PCa in this population. We investigated whether the T allele of rs72725854 is associated with PCa family history and age at diagnosis, characteristics known to have a strong genetic component. Analyses were performed using a sample of 9,052 cases and 8,595 controls from the African Ancestry Prostate Cancer (AAPC) GWAS Consortium and the ELLIPSE/PRACTICAL OncoArray Consortium. Participants were unselected for PCa family history. Among cases, 23.7% carried at least one copy of the T allele versus 11.6% of controls. The OR was 2.29 (95% CI=2.10–2.49) for TA heterozygotes and 5.04 (95% CI=3.36–7.55) for TT homozygotes. The percentage of cases carrying the T allele was significantly greater for men with a PCa family history (27.4% vs. 22.7% without a family history, p=0.002) and for men diagnosed <60 (28.2% vs. 21.6% if over ≥60, p=0.002). The mean age at diagnosis for men with the TT genotype was 61.1 years (sd=8.7), compared to 62.7 (sd=9.1) for TA heterozygotes and 64.3 (sd=8.9) for AA homozygotes (p=5.7E-14). Carrier frequency was highest among men with both a positive family history and an early diagnosis (30.8%). The T allele was also over-represented in cases with more advanced PCa, with carrier frequencies ranging from 26% for lethal PCa (metastatic disease, PSA>100 ng/ml or death from PCa), 25.4% for high-risk disease (stage T3/T4, Gleason 8-10, or PSA=20-100 ng/ml), 24.6% for intermediate-risk disease (Gleason=7, stage T1/T2, and PSA=10-20 ng/ml), and 21.4% for low-risk disease (Gleason<7, stage T1/T2, and PSA<10 ng/ml) (p=0.026). We also examined whether the risk allele is over-represented in 144 men from PCa families, with multiple first- and/or second-degree relatives with PCa or men diagnosed with PCa ≤55 years old. Among affected probands, 32.7% carried the risk allele, with 3.5% being homozygous carriers. The OR for TA heterozygotes and TT homozygotes was 3.41 (95% CI=2.33–4.98) and 11.06 (95% CI=3.92–31.18), respectively. Among men without a family history, the absolute risk for PCa by age 60 for non-risk allele carriers was 4.3%, compared to 9.0% and 15.6% for TA heterozygotes and TT homozygotes, respectively. Absolute risks by age 60 were higher among men with a family history of prostate cancer, reaching 9.0% for non-risk allele carriers, compared to 20.8% and 37.7% for TA heterozygotes and TT homozygotes, respectively. Given the high PCa risk conveyed by rs72725854 and the greater frequency of the allele in men with more aggressive and lethal disease, carriers of the risk allele would benefit from earlier and more regular PSA screening. Citation Format: Burcu F. Darst, 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, Jong Y. Park, Wei Zheng, Elaine A. Ostrander, Shiv Srivastava, John Carpten, Thomas A. Sellers, Maureen Sanderson, Dana C. Crawford, Olivier Cussenot, Jennifer Cullen, Rick A. Kittles, Jianfeng Xu, Zsofia Kote-Jarai, Luc Multigner, Marie-Elise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Adam S. Kibel, Eric A. Klein, Phyllis J. Goodman, Jennifer J. Hu, Graham Casey, Anselm J. Hennis, Ian M. Thompson, Robin Leach, James L. Mohler, Elizabeth T. 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 A. Cooney, William J. Blot, David V. Conti, Christopher A. Haiman. A germline variant at 8q24 contributes to familial clustering of prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3517.
