Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.
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ICR Authors
Authors
Chen, F
Madduri, RK
Rodriguez, AA
Darst, BF
Chou, A
Sheng, X
Wang, A
Shen, J
Saunders, EJ
Rhie, SK
Bensen, JT
Ingles, SA
Kittles, RA
Strom, SS
Rybicki, BA
Nemesure, B
Isaacs, WB
Stanford, JL
Zheng, W
Sanderson, M
John, EM
Park, JY
Xu, J
Wang, Y
Berndt, SI
Huff, CD
Yeboah, ED
Tettey, Y
Lachance, J
Tang, W
Rentsch, CT
Cho, K
Mcmahon, BH
Biritwum, RB
Adjei, AA
Tay, E
Truelove, A
Niwa, S
Sellers, TA
Yamoah, K
Murphy, AB
Crawford, DC
Patel, AV
Bush, WS
Aldrich, MC
Cussenot, O
Petrovics, G
Cullen, J
Neslund-Dudas, CM
Stern, MC
Kote-Jarai, Z
Govindasami, K
Cook, MB
Chokkalingam, AP
Hsing, AW
Goodman, PJ
Hoffmann, TJ
Drake, BF
Hu, JJ
Keaton, JM
Hellwege, JN
Clark, PE
Jalloh, M
Gueye, SM
Niang, L
Ogunbiyi, O
Idowu, MO
Popoola, O
Adebiyi, AO
Aisuodionoe-Shadrach, OI
Ajibola, HO
Jamda, MA
Oluwole, OP
Nwegbu, M
Adusei, B
Mante, S
Darkwa-Abrahams, A
Mensah, JE
Diop, H
Van Den Eeden, SK
Blanchet, P
Fowke, JH
Casey, G
Hennis, AJ
Lubwama, A
Thompson, IM
Leach, R
Easton, DF
Preuss, MH
Loos, RJ
Gundell, SM
Wan, P
Mohler, JL
Fontham, ET
Smith, GJ
Taylor, JA
Srivastava, S
Eeles, RA
Carpten, JD
Kibel, AS
Multigner, L
Parent, M-É
Menegaux, F
Cancel-Tassin, G
Klein, EA
Andrews, C
Rebbeck, TR
Brureau, L
Ambs, S
Edwards, TL
Watya, S
Chanock, SJ
Witte, JS
Blot, WJ
Michael Gaziano, J
Justice, AC
Conti, DV
Haiman, CA
Madduri, RK
Rodriguez, AA
Darst, BF
Chou, A
Sheng, X
Wang, A
Shen, J
Saunders, EJ
Rhie, SK
Bensen, JT
Ingles, SA
Kittles, RA
Strom, SS
Rybicki, BA
Nemesure, B
Isaacs, WB
Stanford, JL
Zheng, W
Sanderson, M
John, EM
Park, JY
Xu, J
Wang, Y
Berndt, SI
Huff, CD
Yeboah, ED
Tettey, Y
Lachance, J
Tang, W
Rentsch, CT
Cho, K
Mcmahon, BH
Biritwum, RB
Adjei, AA
Tay, E
Truelove, A
Niwa, S
Sellers, TA
Yamoah, K
Murphy, AB
Crawford, DC
Patel, AV
Bush, WS
Aldrich, MC
Cussenot, O
Petrovics, G
Cullen, J
Neslund-Dudas, CM
Stern, MC
Kote-Jarai, Z
Govindasami, K
Cook, MB
Chokkalingam, AP
Hsing, AW
Goodman, PJ
Hoffmann, TJ
Drake, BF
Hu, JJ
Keaton, JM
Hellwege, JN
Clark, PE
Jalloh, M
Gueye, SM
Niang, L
Ogunbiyi, O
Idowu, MO
Popoola, O
Adebiyi, AO
Aisuodionoe-Shadrach, OI
Ajibola, HO
Jamda, MA
Oluwole, OP
Nwegbu, M
Adusei, B
Mante, S
Darkwa-Abrahams, A
Mensah, JE
Diop, H
Van Den Eeden, SK
Blanchet, P
Fowke, JH
Casey, G
Hennis, AJ
Lubwama, A
Thompson, IM
Leach, R
Easton, DF
Preuss, MH
Loos, RJ
Gundell, SM
Wan, P
Mohler, JL
Fontham, ET
Smith, GJ
Taylor, JA
Srivastava, S
Eeles, RA
Carpten, JD
Kibel, AS
Multigner, L
Parent, M-É
Menegaux, F
Cancel-Tassin, G
Klein, EA
Andrews, C
Rebbeck, TR
Brureau, L
Ambs, S
Edwards, TL
Watya, S
Chanock, SJ
Witte, JS
Blot, WJ
Michael Gaziano, J
Justice, AC
Conti, DV
Haiman, CA
Document Type
Journal Article
Date
2023-02-27
Date Accepted
2023-01-24
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.
Citation
European Urology, 2023, pp. S0302-2838(23)02561-7 -
Source Title
European Urology
Publisher
ELSEVIER
ISSN
0302-2838
eISSN
1873-7560
1873-7560
1873-7560
Collections
Research Team
Oncogenetics