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.; 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. JR; 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 ORCID: https://orcid.org/0000-0002-4196-3773; 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.; Gaziano, Michael J.; Justice, Amy C.; Conti, David V. et 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 , vol. 84 , nº 1. pp. 13-21. DOI: 10.1016/j.eururo.2023.01.022.

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Résumé

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.

Type de document:	Article
Mots-clés libres:	African ancestry; Aggressive prostate cancer; Polygenic risk score; Prostate cancer; Susceptibility loci
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	08 déc. 2023 21:55
Dernière modification:	22 mars 2024 13:00
URI:	https://espace.inrs.ca/id/eprint/13358

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