Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.
Chen, Fei;
Madduri, Ravi K;
Rodriguez, Alex A;
Darst, Burcu F;
Chou, Alisha;
Sheng, Xin;
Wang, Anqi;
Shen, Jiayi;
Saunders, Edward J;
Rhie, Suhn K;
+108 more...Bensen, Jeannette T;
Ingles, Sue A;
Kittles, Rick A;
Strom, Sara S;
Rybicki, Benjamin A;
Nemesure, Barbara;
Isaacs, William B;
Stanford, Janet L;
Zheng, Wei;
Sanderson, Maureen;
John, Esther M;
Park, Jong Y;
Xu, Jianfeng;
Wang, Ying;
Berndt, Sonja I;
Huff, Chad D;
Yeboah, Edward D;
Tettey, Yao;
Lachance, Joseph;
Tang, Wei;
Rentsch, Christopher T;
Cho, Kelly;
Mcmahon, Benjamin H;
Biritwum, Richard B;
Adjei, Andrew A;
Tay, Evelyn;
Truelove, Ann;
Niwa, Shelley;
Sellers, Thomas A;
Yamoah, Kosj;
Murphy, Adam B;
Crawford, Dana C;
Patel, Alpa V;
Bush, William S;
Aldrich, Melinda C;
Cussenot, Olivier;
Petrovics, Gyorgy;
Cullen, Jennifer;
Neslund-Dudas, Christine M;
Stern, Mariana C;
Kote-Jarai, Zsofia;
Govindasami, Koveela;
Cook, Michael B;
Chokkalingam, Anand P;
Hsing, Ann W;
Goodman, Phyllis J;
Hoffmann, Thomas J;
Drake, Bettina F;
Hu, Jennifer J;
Keaton, Jacob M;
Hellwege, Jacklyn N;
Clark, Peter E;
Jalloh, Mohamed;
Gueye, Serigne M;
Niang, Lamine;
Ogunbiyi, Olufemi;
Idowu, Michael O;
Popoola, Olufemi;
Adebiyi, Akindele O;
Aisuodionoe-Shadrach, Oseremen I;
Ajibola, Hafees O;
Jamda, Mustapha A;
Oluwole, Olabode P;
Nwegbu, Maxwell;
Adusei, Ben;
Mante, Sunny;
Darkwa-Abrahams, Afua;
Mensah, James E;
Diop, Halimatou;
Van Den Eeden, Stephen K;
Blanchet, Pascal;
Fowke, Jay H;
Casey, Graham;
Hennis, Anselm J;
Lubwama, Alexander;
Thompson, Ian M;
Leach, Robin;
Easton, Douglas F;
Preuss, Michael H;
Loos, Ruth J;
Gundell, Susan M;
Wan, Peggy;
Mohler, James L;
Fontham, Elizabeth T;
Smith, Gary J;
Taylor, Jack A;
Srivastava, Shiv;
Eeles, Rosaline A;
Carpten, John D;
Kibel, Adam S;
Multigner, Luc;
Parent, Marie-Élise;
Menegaux, Florence;
Cancel-Tassin, Geraldine;
Klein, Eric A;
Andrews, Caroline;
Rebbeck, Timothy R;
Brureau, Laurent;
Ambs, Stefan;
Edwards, Todd L;
Watya, Stephen;
Chanock, Stephen J;
Witte, John S;
Blot, William J;
Michael Gaziano, J;
Justice, Amy C;
Conti, David V;
Haiman, Christopher A;
(2023)
Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.
European Urology.
S0302-2838(23)02561-7-.
ISSN 0302-2838
DOI: https://doi.org/10.1016/j.eururo.2023.01.022
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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.
Description: This is an author accepted manuscript version of an article accepted for publication, and following peer review. Please be aware that minor differences may exist between this version and the final version if you wish to cite from it.
Licence: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Description: This is an author accepted manuscript version of an article accepted for publication, and following peer review. Please be aware that minor differences may exist between this version and the final version if you wish to cite from it.
Licence: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
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