Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry
Creators: name: Witte, J.S.
name: Chanock, S.J.
name: Popoola, O.
name: Madduri, R.K.
name: Adjei, A.A.
name: Chen, F.
name: Menegaux, F.
name: Blot, W.J.
name: Rentsch, C.T.
name: Bensen, J.T.
name: Clark, P.E.
name: Kittles, R.A.
name: Hennis, A.J.
name: Tay, E.
name: Saunders, E.J.
name: Blanchet, P.
name: Truelove, A.
name: Fontham, E.T.
name: Loos, R.J.
name: Petrovics, G.
name: Stern, M.C.
name: Kibel, A.S.
name: Hu, J.J.
name: Stanford, J.L.
name: Adebiyi, A.O.
name: Gaziano, J.M.
name: Multigner, L.
name: Taylor, J.A.
name: Watya, S.
name: Zheng, W.
name: Biritwum, R.B.
name: Parent, M.-É.
name: Sanderson, M.
name: Murphy, A.B.
name: Crawford, D.C.
name: Ogunbiyi, O.
name: Lubwama, A.
name: Thompson, I.M., Jr.
name: Gundell, S.M.
name: Lachance, J.
name: John, E.M.
name: Drake, B.F.
name: Park, J.Y.
name: Aisuodionoe-Shadrach, O.I.
name: Leach, R.
name: Ajibola, H.O.
name: Strom, S.S.
name: Justice, A.C.
name: Jamda, M.A.
name: Oluwole, O.P.
name: Srivastava, S.
name: Carpten, J.D.
name: Gueye, S.M.
name: Sellers, T.A.
name: Niang, L.
name: Patel, A.V.
name: Yamoah, K.
name: Sheng, X.
name: Chou, A.
name: Shen, J.
name: Wang, A.
name: Cho, K.
name: Mcmahon, B.H.
name: Easton, D.F.
name: Preuss, M.H.
name: Cullen, J.
name: Hoffmann, T.J.
name: Mensah, J.E.
name: Darkwa-Abrahams, A.
name: Neslund-Dudas, C.M.
name: Eeles, R.A.
name: Nwegbu, M.
name: Rhie, S.K.
name: Xu, J.
name: Goodman, P.J.
name: Cancel-Tassin, G.
name: Ingles, S.A.
name: Nemesure, B.
name: Klein, E.A.
name: Yeboah, E.D.
name: Hellwege, J.N.
name: Tettey, Y.
name: Darst, B.F.
name: Brureau, L.
name: Rodriguez, A.A.
name: Bush, W.S.
name: Tang, W.
name: Ambs, S.
name: Diop, H.
name: Jalloh, M.
name: Van Den Eeden, S.K.
name: Andrews, C.
name: Wan, P.
name: Wang, Y.
name: Rebbeck, T.R.
name: Mohler, J.L.
name: Berndt, S.I.
name: Niwa, S.
name: Aldrich, M.C.
name: Hsing, A.W.
name: Cussenot, O.
name: Haiman, C.A.
name: Conti, D.V.
name: Mante, S.
name: Adusei, B.
name: Cook, M.B.
name: Kote-Jarai, Z.
name: Rybicki, B.A.
name: Huff, C.D.
name: Keaton, J.M.
name: Chokkalingam, A.P.
name: Isaacs, W.B.
name: Govindasami, K.
name: Smith, G.J.
name: Fowke, J.H.
name: Edwards, T.L.
name: Casey, G.
name: Idowu, M.O.
Publisher: name: Elsevier B.V.
Year: 2023

description: 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 19 378 cases and 61 620 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] &gt;3 and &gt;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.