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

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; Hayes, Vanessa M.

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

Kazzem Gheybi, Pamela X. Y. Soh, Jue Jiang, Tumisang M. N. Mbeki, Melanie Louw, Daniel Burns, Piyushkumar Mundra, Daria Kiriy, Md. Mehedi Hasan, Weerachai Jaratlerdsiri, Maphuti Tebogo Lebelo, Raymond A. Campbell, Mulalo B. Radzuma, Mukudeni Nenzhelele, Muvhulawa Obida, Martin Obida, Winstar M. Ombuki, Micah O. Oyaro, Sean M. Patrick, Massimo Loda, David C. Wedge, Robert G. Bristow, Daniel S. Brewer, Colin S. Cooper, Jüri Reimand, Geraldine Cancel-Tassin, Olivier Cussenot, Chris M. Hovens, Niall M. Cocoran, Phillip D. Stricker, Thorsten Schlomm, Gail S. Prins, Karina Dalsgaard Sørensen, Joachim Weischenfeldt, Shingai B. A. Mutambirwa, Peter M. Ngugi, David M. Thomas, Zsofia Kote-Jarai, Rosalind A. Eeles, M. S. Riana Bornman and Vanessa M. Hayes ()
Additional contact information
Kazzem Gheybi: University of Sydney
Pamela X. Y. Soh: University of Sydney
Jue Jiang: University of Sydney
Tumisang M. N. Mbeki: University of Pretoria
Melanie Louw: National Health Laboratory Services
Daniel Burns: The Institute of Cancer Research
Piyushkumar Mundra: University of New South Wales Sydney
Daria Kiriy: University of Copenhagen
Md. Mehedi Hasan: University of Sydney
Weerachai Jaratlerdsiri: University of Sydney
Maphuti Tebogo Lebelo: University of Pretoria
Raymond A. Campbell: University of Pretoria
Mulalo B. Radzuma: Medunsa
Mukudeni Nenzhelele: Shayandima
Muvhulawa Obida: University of Pretoria
Martin Obida: University of Pretoria
Winstar M. Ombuki: University of Nairobi
Micah O. Oyaro: University of Nairobi
Sean M. Patrick: University of Pretoria
Massimo Loda: Weil Cornell Medicine
David C. Wedge: University of Manchester
Robert G. Bristow: University of Manchester
Daniel S. Brewer: University of East Anglia
Colin S. Cooper: The Institute of Cancer Research
Jüri Reimand: Ontario Institute for Cancer Research
Geraldine Cancel-Tassin: Hospital Tenon
Olivier Cussenot: Hospital Tenon
Chris M. Hovens: The Victorian Comprehensive Cancer Centre
Niall M. Cocoran: The Victorian Comprehensive Cancer Centre
Phillip D. Stricker: St Vincent’s Prostate Cancer Research Centre
Thorsten Schlomm: Charité Universitätsmedizin Berlin
Gail S. Prins: University of Illinois at Chicago
Karina Dalsgaard Sørensen: Aarhus University Hospital
Joachim Weischenfeldt: University of Copenhagen
Shingai B. A. Mutambirwa: Medunsa
Peter M. Ngugi: University of Nairobi
David M. Thomas: University of New South Wales Sydney
Zsofia Kote-Jarai: The Institute of Cancer Research
Rosalind A. Eeles: The Institute of Cancer Research
M. S. Riana Bornman: University of Pretoria
Vanessa M. Hayes: University of Sydney

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63865-6

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