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

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Gheybi, Kazzem, Soh, Pamela X. Y., Jiang, Jue, Mbeki, Tumisang M. N., Louw, Melanie, Burns, Daniel, Mundra, Piyushkumar, Kiriy, Daria, Hasan, Md. Mehedi, Jaratlerdsiri, Weerachai, Lebelo, Maphuti Tebogo, Campbell, Raymond A., Radzuma, Mulalo B., Nenzhelele, Mukudeni, Obida, Muvhulawa, Obida, Martin, Ombuki, Winstar M., Oyaro, Micah O., Patrick, Sean M., Loda, Massimo, Wedge, David C., Bristow, Robert G., Brewer, Daniel S., Cooper, Colin S., Reimand, Jüri, Cancel-Tassin, Geraldine, Cussenot, Olivier, Hovens, Chris M., Cocoran, Niall M., Stricker, Phillip D., Schlomm, Thorsten, Prins, Gail S., Sørensen, Karina Dalsgaard, Weischenfeldt, Joachim, Mutambirwa, Shingai B. A., Ngugi, Peter M., Thomas, David M., Kote-Jarai, Zsofia, Eeles, Rosalind A., Bornman, M. S. Riana and Hayes, Vanessa M. and The Pan Prostate Cancer Group (PPCG), HEROIC PCaPH Africa1K (2025) Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry. Nature Communications, 16. ISSN 2041-1723

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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.

Item Type: Article
Additional Information: See the published article for information on data and code availability, and for funding information.
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
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Depositing User: LivePure Connector
Date Deposited: 03 Oct 2025 10:30
Last Modified: 30 Oct 2025 10:31
URI: https://ueaeprints.uea.ac.uk/id/eprint/100614
DOI: 10.1038/s41467-025-63865-6

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