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 ; +108 more... Jeannette T Bensen ; Sue A Ingles ; Rick A Kittles ; Sara S Strom ; Benjamin A Rybicki ; 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 ORCID logo ; 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 ; 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 ; (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, 84 (1). pp. 13-21. ISSN 0302-2838 DOI: 10.1016/j.eururo.2023.01.022
Copy

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.


picture_as_pdf
Chen_etal_2023_Evidence-of-novel-susceptibility-variants.pdf
subject
Accepted Version
Available under Creative Commons: Attribution-NonCommercial-No Derivative Works 4.0

View Download
picture_as_pdf

Supplemental Material


Atom BibTeX OpenURL ContextObject in Span Multiline CSV OpenURL ContextObject Dublin Core Dublin Core MPEG-21 DIDL Data Cite XML EndNote HTML Citation JSON MARC (ASCII) MARC (ISO 2709) METS MODS RDF+N3 RDF+N-Triples RDF+XML RIOXX2 XML Reference Manager Refer Simple Metadata ASCII Citation EP3 XML
Export

Downloads