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; 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; 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 Jr; 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

doi:10.1016/j.eururo.2023.01.022

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

Eur Urol. 2023 Jul;84(1):13-21. doi: 10.1016/j.eururo.2023.01.022. Epub 2023 Mar 3.

Authors

Fei Chen¹, Ravi K Madduri², Alex A Rodriguez², Burcu F Darst³, Alisha Chou¹, Xin Sheng¹, Anqi Wang¹, Jiayi Shen¹, Edward J Saunders⁴, Suhn K Rhie⁵, Jeannette T Bensen⁶, Sue A Ingles¹, Rick A Kittles⁷, Sara S Strom⁸, Benjamin A Rybicki⁹, Barbara Nemesure¹⁰, William B Isaacs¹¹, Janet L Stanford¹², Wei Zheng¹³, Maureen Sanderson¹⁴, Esther M John¹⁵, Jong Y Park¹⁶, Jianfeng Xu¹⁷, Ying Wang¹⁸, Sonja I Berndt¹⁹, Chad D Huff⁸, Edward D Yeboah²⁰, Yao Tettey²¹, Joseph Lachance²², Wei Tang²³, Christopher T Rentsch²⁴, Kelly Cho²⁵, Benjamin H Mcmahon²⁶, Richard B Biritwum²⁷, Andrew A Adjei²⁸, Evelyn Tay²⁷, Ann Truelove²⁹, Shelley Niwa²⁹, Thomas A Sellers¹⁶, Kosj Yamoah³⁰, Adam B Murphy³¹, Dana C Crawford³², Alpa V Patel¹⁸, William S Bush³², Melinda C Aldrich³³, Olivier Cussenot³⁴, Gyorgy Petrovics³⁵, Jennifer Cullen³⁶, Christine M Neslund-Dudas⁹, Mariana C Stern¹, Zsofia Kote-Jarai⁴, Koveela Govindasami⁴, Michael B Cook¹⁹, Anand P Chokkalingam³⁷, Ann W Hsing¹⁵, Phyllis J Goodman³⁸, Thomas J Hoffmann³⁹, Bettina F Drake⁴⁰, Jennifer J Hu⁴¹, Jacob M Keaton⁴², Jacklyn N Hellwege⁴³, Peter E Clark⁴⁴, Mohamed Jalloh⁴⁵, Serigne M Gueye⁴⁵, Lamine Niang⁴⁵, Olufemi Ogunbiyi⁴⁶, Michael O Idowu⁴⁶, Olufemi Popoola⁴⁶, Akindele O Adebiyi⁴⁶, Oseremen I Aisuodionoe-Shadrach⁴⁷, Hafees O Ajibola⁴⁷, Mustapha A Jamda⁴⁷, Olabode P Oluwole⁴⁷, Maxwell Nwegbu⁴⁷, Ben Adusei⁴⁸, Sunny Mante⁴⁸, Afua Darkwa-Abrahams²⁷, James E Mensah²⁷, Halimatou Diop⁴⁹, Stephen K Van Den Eeden⁵⁰, Pascal Blanchet⁵¹, Jay H Fowke⁵², Graham Casey⁵³, Anselm J Hennis¹⁰, Alexander Lubwama⁵⁴, Ian M Thompson Jr⁵⁵, Robin Leach⁵⁶, Douglas F Easton⁵⁷, Michael H Preuss⁵⁸, Ruth J Loos⁵⁸, Susan M Gundell¹, Peggy Wan¹, James L Mohler⁵⁹, Elizabeth T Fontham⁶⁰, Gary J Smith⁶¹, Jack A Taylor⁶², Shiv Srivastava⁶³, Rosaline A Eeles⁶⁴, John D Carpten⁶⁵, Adam S Kibel⁶⁶, Luc Multigner⁶⁷, Marie-Élise Parent⁶⁸, Florence Menegaux⁶⁹, Geraldine Cancel-Tassin³⁴, Eric A Klein⁷⁰, Caroline Andrews⁷¹, Timothy R Rebbeck⁷², Laurent Brureau⁵¹, Stefan Ambs²³, Todd L Edwards¹³, Stephen Watya⁵⁴, Stephen J Chanock¹⁹, John S Witte⁷³, William J Blot⁷⁴, J Michael Gaziano⁷⁵, Amy C Justice⁷⁶, David V Conti¹, Christopher A Haiman⁷⁷

Affiliations

¹ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Argonne National Laboratory, Lemont, IL, USA.
³ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴ The Institute of Cancer Research, London, UK.
⁵ Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Department of Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
⁸ Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
¹⁰ Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
¹¹ James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA.
¹² Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹³ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁴ Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, USA.
¹⁵ Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
¹⁷ Program for Personalized Cancer Care and Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
¹⁸ Department of Population Science, American Cancer Society, Kennesaw, GA, USA.
¹⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
²⁰ University of Ghana Medical School, Accra, Ghana.
²¹ Department of Pathology, University of Ghana, Accra, Ghana; Korle Bu Teaching Hospital, Accra, Ghana.
²² School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA.
²³ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
²⁴ Yale School of Medicine, New Haven, CT, USA; VA Connecticut Healthcare System, West Haven, CT, USA; Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
²⁵ Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; VA Boston Healthcare System, Jamaica Plain, MA, USA.
²⁶ Theoretical Biology Division, Los Alamos National Lab, Los Alamos, NM, USA.
²⁷ Korle Bu Teaching Hospital, Accra, Ghana.
²⁸ Department of Pathology, University of Ghana Medical School, Accra, Ghana.
²⁹ Westat, Rockville, MD, USA.
³⁰ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA; Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA.
³¹ Department of Urology, Northwestern University, Chicago, IL, USA.
³² Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
³³ Division of Epidemiology, Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁴ Department of Urology and Predictive Onco-Urology Group, Sorbonne Université, GRC 5 Predictive Onco-Urology, APHP-Sorbonne Université, Paris, France; CeRePP, Tenon Hospital, Paris, France.
³⁵ Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
³⁶ Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA; Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
³⁷ School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
³⁸ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³⁹ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
⁴⁰ Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, USA.
⁴¹ The University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
⁴² Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁴³ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Nashville, TN, USA.
⁴⁴ Atrium Health/Levine Cancer Institute, Charlotte, NC, USA.
⁴⁵ Hôpital Général Idrissa Pouye, Dakar, Senegal.
⁴⁶ College of Medicine, University of Ibadan and University College Hospital, Ibadan, Nigeria.
⁴⁷ College of Health Sciences, University of Abuja, University of Abuja Teaching Hospital and Cancer Science Center, Abuja, Nigeria.
⁴⁸ 37 Military Hospital, Accra, Ghana.
⁴⁹ Laboratoires Bacteriologie et Virologie, Hôpital Aristide Le Dantec, Dakar, Senegal.
⁵⁰ Division of Research, Kaiser Permanente, Northern California, Oakland, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
⁵¹ CHU de Pointe-à-Pitre, Univ Antilles, Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail), Pointe-à-Pitre, Guadeloupe, France.
⁵² Department of Preventive Medicine, Division of Epidemiology, The University of Tennessee Health Science Center, Memphis, TN, USA.
⁵³ Department of Public Health Science, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁵⁴ Uro Care, Kampala, Uganda.
⁵⁵ CHRISTUS Santa Rosa Medical Center Hospital, San Antonio, TX, USA.
⁵⁶ Department of Urology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁵⁷ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
⁵⁸ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA.
⁶⁰ School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
⁶¹ Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA.
⁶² Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
⁶³ Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
⁶⁴ The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK.
⁶⁵ Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶⁶ Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶⁷ Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail), Rennes, France.
⁶⁸ Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, Laval, QC, Canada.
⁶⁹ Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif Cédex, France; Paris-Sud University, Villejuif Cédex, France.
⁷⁰ Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
⁷¹ Harvard TH Chan School of Public Health and Division of Population Sciences, Dana Farber Cancer Institute, Boston, MA, USA; Glickman Urological & Kidney Institute, Cleveland, OH, USA.
⁷² Harvard TH Chan School of Public Health and Division of Population Sciences, Dana Farber Cancer Institute, Boston, MA, USA.
⁷³ Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
⁷⁴ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; International Epidemiology Institute, Rockville, MD, USA.
⁷⁵ Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA.
⁷⁶ Yale School of Medicine, New Haven, CT, USA; VA Connecticut Healthcare System, West Haven, CT, USA.
⁷⁷ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: haiman@usc.edu.

PMID: 36872133
PMCID: PMC10424812 (available on 2024-07-01)
DOI: 10.1016/j.eururo.2023.01.022

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.

Keywords: African ancestry; Aggressive prostate cancer; Polygenic risk score; Prostate cancer; Susceptibility loci.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Black People / genetics
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Male
Prostatic Neoplasms* / epidemiology
Prostatic Neoplasms* / genetics
Risk Factors

Abstract

Publication types

MeSH terms

Grants and funding