Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry

Prostate cancer (PCa) germline testing, while gaining momentum, is ancestry restrictive and African exclusive. Through whole genome sequencing for 217 African ancestral cases (186 southern African, 31 Pan representative), we identify 172 potentially pathogenic variants in 78 DNA damage repair or PCa related genes. Prevalence for reported (13/217, 5.99%) and cumulative predicted (24/217, 11.06%) variants of significance (11 genes) falls below that reported for non-Africans. Conversely, BRCA1, HOXB13, CDK12, MLH1, MSH2, and BRIP1 remain unimpacted. Through pathogenic ranking based on variant frequency and functionality, clinical presentation and tumour-matched biallelic inactivation, top-ranked candidates include PREX2, POLE, FAT1, BRCA2, POLQ, LRP1B and ATM. Besides notable impact of DNA polymerases, including POLG, Fanconi anaemia genes include FANCD2, FANCA, FANCG, ERCC4, FANCE and FANCI, while DNA mismatch repair genes MSH3 and PMS1 outranked known namesakes MSH6 and PMS2. This study provides insights into the spectrum of African-relevant potentially pathogenic PCa variants, highlighting much-needed gene candidates for ancestry-inclusive germline testing.

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Publication Details

Journal
Nature Communications
Published
2025-10-02
DOI
https://doi.org/10.1038/s41467-025-63865-6
Citations
5
Primary Topic
Prostate Cancer Treatment and Research
Type
article
Field-Weighted Citation Impact
7.59

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Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry

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Nature Communications
Prostate Cancer Treatment and Research
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article

Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry

Ikenna Madueke, Kevin Cheng, Shingai B.A. Mutambirwa, David C. Wedge, Golda Stellmacher, Thorsten Schlomm, Phillip D. Stricker, Francesco Favero, G. Steven Bova, Clarissa Gerhäuser, Diogo Pellegrina, Piyushkumar A. Mundra, Willis Oyieko, Rosalind A. Eeles, Géraldine Cancel‐Tassin, Korawich Uthayopas, Lúcio Queiroz, Daria Kiriy, I.E.J. Barnhoorn, Pamela X. Y. Soh, G. Maria Jakobsdottir, Philippe Lamy, Kangping Zhou, Robert G. Bristow, Giuseppe Fanelli, Jue Jiang, Daniel Burns, Vincent J. Gnanapragasam, Eddie L. Imada, Andreas Gruber, Daniel M. Moreira, Maria Argos, Takafumi N. Yamaguchi, Lynn Birch, Abraham Gihawi, Avraam Tapinos, P M Ngugi, Kazzem Gheybi, Tobias Rausch, Joyce Shirinde, Etsehiwot G. Girma, Joachim Weischenfeldt, Atef Sahli, Maphuti Tebogo Lebelo, Weerachai Jaratlerdsiri, Gail S. Prins, Housheng Hansen He, Zsofia Kote‐Jarai, Mark N. Brook, Anthony T. Papenfuss, Melanie Louw, Bernard J. Pope, Chol-Hee Jung, Benedikt Brors, David M. Thomas, Francesca Khani, Raymond Campbell, Md Mehedi Hasan, Douglas I. Walker, Yaobo Xu, Massimo Loda, Anis Hamid, Reginald Menoe, Jenna Craddock, Hagen E. A. Förtsch, Muvhulawa Obida, Ramyar Molania, Luigi Marchionni, Christopher M. Hovens, Edwin O O Walong, Karina D. Sørensen, Claudio Zanettini, Daniel S. Brewer, Sebastian Uhrig, Jüri Reimand, Valerie F. Holmes, Mukudeni Nenzhelele, Gregory Leeman, Tingting Gong, Niall M. Corcoran, Colin S. Cooper, Bruce G. Robinson, Mulalo B. Radzuma, Micah Oyaro, Eva F. Jensby, Adam P. Butler, Ruotian Huang, Olivier Cussenot, Winstar Mokua Ombuki, Muriuki Elias Nyaga, Allan Yienya, Githui Sheila Wanjiku, Niall M. Cocoran, Weerachai Jaratlersiri, Jessie Gamxamub, Umuna Maendo
article en
5 citations

Abstract

Prostate cancer (PCa) germline testing, while gaining momentum, is ancestry restrictive and African exclusive. Through whole genome sequencing for 217 African ancestral cases (186 southern African, 31 Pan representative), we identify 172 potentially pathogenic variants in 78 DNA damage repair or PCa related genes. Prevalence for reported (13/217, 5.99%) and cumulative predicted (24/217, 11.06%) variants of significance (11 genes) falls below that reported for non-Africans. Conversely, BRCA1, HOXB13, CDK12, MLH1, MSH2, and BRIP1 remain unimpacted. Through pathogenic ranking based on variant frequency and functionality, clinical presentation and tumour-matched biallelic inactivation, top-ranked candidates include PREX2, POLE, FAT1, BRCA2, POLQ, LRP1B and ATM. Besides notable impact of DNA polymerases, including POLG, Fanconi anaemia genes include FANCD2, FANCA, FANCG, ERCC4, FANCE and FANCI, while DNA mismatch repair genes MSH3 and PMS1 outranked known namesakes MSH6 and PMS2. This study provides insights into the spectrum of African-relevant potentially pathogenic PCa variants, highlighting much-needed gene candidates for ancestry-inclusive germline testing.

Nature CommunicationsVol. 16(1)
National Health Laboratory Service (ZA), Boston University (US), University of East Anglia (GB), Ontario Institute for Cancer Research (CA), University of Copenhagen (DK), University of Nairobi (KE), Prostate Cancer Foundation of Australia (AU), The University of Sydney (AU), The Royal Melbourne Hospital (AU), Royal Marsden NHS Foundation Trust (GB), University Health Network (CA), Institute of Cancer Research (GB), Emory University (US), University of California, Los Angeles (US), The University of Melbourne (AU), Tampere University (FI), German Cancer Research Center (DE), University of Toronto (CA), University of Konstanz (DE), University of the Witwatersrand (ZA), Maseno University (KE), Walter and Eliza Hall Institute of Medical Research (AU), Aarhus University (DK), Cornell University (US), Botswana International University of Science and Technology (BW), University of Namibia (NA), Heidelberg University (DE), Norwich Research Park (GB), Manchester Academic Health Science Centre (GB), Cancer Institute of New South Wales (AU), University Hospital Heidelberg (DE), Aarhus University Hospital (DK), Sefako Makgatho Health Sciences University (ZA), Cambridge University Hospitals NHS Foundation Trust (GB), Wellcome Sanger Institute (GB), Copenhagen University Hospital (DK), Dr George Mukhari Hospital (ZA), Princess Margaret Cancer Centre (CA), University of Manchester (GB), Meru University of Science and Technology (KE), Jaramogi Oginga Odinga University of Science and Technology (KE), UNSW Sydney (AU), Melbourne Bioinformatics (AU), University of Illinois Chicago (US), Sorbonne Université (FR), Assistance Publique – Hôpitaux de Paris (FR), Earlham Institute (GB), Victorian Comprehensive Cancer Centre (AU), Children's Cancer Institute Australia (AU), Cancer Research UK Manchester Institute (GB), The Christie NHS Foundation Trust (GB), European Molecular Biology Laboratory (DE), Hearing4all (DE), East African University (KE), Hôpital Tenon (FR), Onco-Urologie Prédictive, University of Pretoria (ZA), Charité - Universitätsmedizin Berlin (DE), Australian Institute of Family Studies (AU), Neuroscience Research Australia (AU), University of Venda (ZA), Heidelberg University (US), Epigenomics (Germany) (DE), KU Leuven (BE)
Prostate Cancer Foundation, Movember Foundation, Royal Marsden NHS Foundation Trust, Cancer Research UK, National Institute for Health and Care Research, Prostate Cancer UK, University of New South Wales, Petre Foundation, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Cancer Institute, Congressionally Directed Medical Research Programs, DOD Prostate Cancer Research Program
Openalex Percentile: Top 2%
Prostate Cancer Treatment and Research
7.59
DOIOpen Access PDFOpenAlex
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