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
Ravi K. Madduri
Alex A. Rodriguez
Burcu F. Darst
Alisha Chou
Xin Sheng
Anqi Wang
Jiayi Shen
Edward J. Saunders
Suhn K. Rhie
Jeannette T. Bensen
Sue A. Ingles
Rick A. Kittles
Sara S. Strom
Benjamin A. Rybicki, Henry Ford HealthFollow
Barbara Nemesure
William B. Isaacs
Janet L. Stanford
Wei Zheng
Maureen Sanderson
Esther M. John
Jong Y. Park
Jianfeng Xu
Ying Wang
Sonja I. Berndt
Chad D. Huff
Edward D. Yeboah
Yao Tettey
Joseph Lachance
Wei Tang
Christopher T. Rentsch
Kelly Cho
Benjamin H. Mcmahon
Richard B. Biritwum
Andrew A. Adjei
Evelyn Tay
Ann Truelove
Shelley Niwa
Thomas A. Sellers
Kosj Yamoah
Adam B. Murphy
Dana C. Crawford
Alpa V. Patel
William S. Bush
Melinda C. Aldrich
Olivier Cussenot
Gyorgy Petrovics
Jennifer Cullen
Christine M. Neslund-Dudas, Henry Ford HealthFollow
Mariana C. Stern
Zsofia Kote-Jarai
Koveela Govindasami
Michael B. Cook
Anand P. Chokkalingam
Ann W. Hsing
Phyllis J. Goodman
Thomas J. Hoffmann
Bettina F. Drake
Jennifer J. Hu
Jacob M. Keaton
Jacklyn N. Hellwege
Peter E. Clark
Mohamed Jalloh
Serigne M. Gueye
Lamine Niang
Olufemi Ogunbiyi
Michael O. Idowu
Olufemi Popoola
Akindele O. Adebiyi
Oseremen I. Aisuodionoe-Shadrach
Hafees O. Ajibola
Mustapha A. Jamda
Olabode P. Oluwole
Maxwell Nwegbu
Ben Adusei
Sunny Mante
Afua Darkwa-Abrahams
James E. Mensah
Halimatou Diop
Stephen K. Van Den Eeden
Pascal Blanchet
Jay H. Fowke
Graham Casey
Anselm J. Hennis
Alexander Lubwama
Ian M. Thompson
Robin Leach
Douglas F. Easton
Michael H. Preuss
Ruth J. Loos
Susan M. Gundell
Peggy Wan
James L. Mohler
Elizabeth T. Fontham
Gary J. Smith
Jack A. Taylor
Shiv Srivastava
Rosaline A. Eeles
John D. Carpten
Adam S. Kibel
Luc Multigner
Marie-Élise Parent
Florence Menegaux
Geraldine Cancel-Tassin
Eric A. Klein
Caroline Andrews
Timothy R. Rebbeck
Laurent Brureau
Stefan Ambs
Todd L. Edwards
Stephen Watya
Stephen J. Chanock
John S. Witte
William J. Blot
J. Michael Gaziano
Amy C. Justice
David V. Conti
Christopher A. Haiman

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European urology


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.

PubMed ID



ePub ahead of print