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Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.

Fei Chen,R. Madduri,Alex Rodriguez,B. Darst,Alisha Chou,Xin Sheng,Anqi Wang,Jiayi Shen,E. Saunders,S. Rhie,J. Bensen,S. Ingles,R. Kittles,S. Strom,B. Rybicki,B. Nemesure,W. Isaacs,J. Stanford,W. Zheng,M. Sanderson,E. John,Jong Y. Park,Jianfeng Xu,Ying Wang,Sonja I. Berndt,C. Huff,E. Yeboah,Y. Tettey,J. Lachance,Wei Tang,C. Rentsch,Kelly Cho,Benjamin H. McMahon,R. Biritwum,A. Adjei,E. Tay,A. Truelove,S. Niwa,T. Sellers,K. Yamoah,Adam B. Murphy,D. Crawford,Alpa V. Patel,W. Bush,M. Aldrich,O. Cussenot,G. Petrovics,J. Cullen,C. Neslund-Dudas,M. Stern,Z. Kote-Jarai,K. Govindasami,M. Cook,A. Chokkalingam,A. Hsing,P. Goodman,T. Hoffmann,B. Drake,Jennifer J. Hu,Jacob M. Keaton,J. Hellwege,Peter E. Clark,M. Jalloh,S. Gueye,L. Niang,O. Ogunbiyi,M. Idowu,Olufemi O. Popoola,A. Adebiyi,O. Aisuodionoe-Shadrach,Hafees O Ajibola,M. Jamda,O. Oluwole,M. Nwegbu,B. Adusei,S. Mante,Afua Darkwa-Abrahams,J. Mensah,H. Diop,S. K. Van Den Eeden,P. Blanchet,J. Fowke,G. Casey,A. Hennis,Alex Lubwama,I. Thompson,R. Leach,D. Easton,Michael H. Preuss,R. Loos,Susan M Gundell,Peggy Wan,J. Mohler,E. Fontham,Gary J. Smith,Jack A. Taylor,S. Srivastava,R. Eeles,J. Carpten,A. Kibel,L. Multigner,M. Parent,F. Menegaux,G. Cancel-Tassin,E. Klein,Caroline Andrews,T. Rebbeck,L. Brureau,S. Ambs,T. Edwards,S. Watya,S. Chanock,J. Witte,W. Blot,J. Michael Gaziano,Amy C. Justice,D. Conti,C. Haiman

Published 2023 in European Urology

ABSTRACT

BACKGROUND Genetic factors play an important role in prostate cancer (PCa) susceptibility. OBJECTIVE To discover common genetic variants contributing to the risk of PCa in men of African ancestry. DESIGN, SETTING, AND PARTICIPANTS We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. RESULTS AND LIMITATIONS Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4). CONCLUSIONS This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. PATIENT SUMMARY In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

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