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; The Pan Prostate Cancer Group (PPCG); HEROIC PCaPH Africa1K; Joachim Weischenfeldt; Shingai B. A. Mutambirwa; Peter M. Ngugi; David M. Thomas; Zsofia Kote-Jarai; Rosalind A. Eeles; M. S. Riana Bornman; Vanessa M. Hayes

doi:10.1038/s41467-025-63865-6

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 LodaDavid 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, The Pan Prostate Cancer Group (PPCG), HEROIC PCaPH Africa1K, Joachim Weischenfeldt, Shingai B. A. Mutambirwa, Peter M. Ngugi, David M. Thomas, Zsofia Kote-Jarai, Rosalind A. Eeles, M. S. Riana Bornman, Vanessa M. Hayes

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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.

Original language	English
Article number	8799
Journal	Nature Communications
Volume	16
DOIs	https://doi.org/10.1038/s41467-025-63865-6
Publication status	Published - 2 Oct 2025

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Gheybi, K., Soh, P. X. Y., Jiang, J., Mbeki, T. M. N., Louw, M., Burns, D., Mundra, P., Kiriy, D., Hasan, M. M., Jaratlerdsiri, W., Lebelo, M. T., Campbell, R. A., Radzuma, M. B., Nenzhelele, M., Obida, M., Obida, M., Ombuki, W. M., Oyaro, M. O., Patrick, S. M., ... Hayes, V. M. (2025). Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry. Nature Communications, 16, Article 8799. https://doi.org/10.1038/s41467-025-63865-6

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title = "Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry",

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.",

author = "Kazzem Gheybi and Soh, {Pamela X. Y.} and Jue Jiang and Mbeki, {Tumisang M. N.} and Melanie Louw and Daniel Burns and Piyushkumar Mundra and Daria Kiriy and Hasan, {Md. Mehedi} and Weerachai Jaratlerdsiri and Lebelo, {Maphuti Tebogo} and Campbell, {Raymond A.} and Radzuma, {Mulalo B.} and Mukudeni Nenzhelele and Muvhulawa Obida and Martin Obida and Ombuki, {Winstar M.} and Oyaro, {Micah O.} and Patrick, {Sean M.} and Massimo Loda and Wedge, {David C.} and Bristow, {Robert G.} and Brewer, {Daniel S.} and Cooper, {Colin S.} and J{\"u}ri Reimand and Geraldine Cancel-Tassin and Olivier Cussenot and Hovens, {Chris M.} and Cocoran, {Niall M.} and Stricker, {Phillip D.} and Thorsten Schlomm and Prins, {Gail S.} and S{\o}rensen, {Karina Dalsgaard} and {The Pan Prostate Cancer Group (PPCG)} and {HEROIC PCaPH Africa1K} and Abraham Gihawi and Joachim Weischenfeldt and Mutambirwa, {Shingai B. A.} and Ngugi, {Peter M.} and Thomas, {David M.} and Zsofia Kote-Jarai and Eeles, {Rosalind A.} and Bornman, {M. S. Riana} and Hayes, {Vanessa M.}",

note = "See the published article for information on data and code availability, and for funding information.",

year = "2025",

month = oct,

day = "2",

doi = "10.1038/s41467-025-63865-6",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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Gheybi, K, Soh, PXY, Jiang, J, Mbeki, TMN, Louw, M, Burns, D, Mundra, P, Kiriy, D, Hasan, MM, Jaratlerdsiri, W, Lebelo, MT, Campbell, RA, Radzuma, MB, Nenzhelele, M, Obida, M, Obida, M, Ombuki, WM, Oyaro, MO, Patrick, SM, Loda, M, Wedge, DC, Bristow, RG, Brewer, DS , Cooper, CS, Reimand, J, Cancel-Tassin, G, Cussenot, O, Hovens, CM, Cocoran, NM, Stricker, PD, Schlomm, T, Prins, GS, Sørensen, KD, The Pan Prostate Cancer Group (PPCG), HEROIC PCaPH Africa1K, Weischenfeldt, J, Mutambirwa, SBA, Ngugi, PM, Thomas, DM, Kote-Jarai, Z, Eeles, RA, Bornman, MSR & Hayes, VM 2025, 'Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry', Nature Communications, vol. 16, 8799. https://doi.org/10.1038/s41467-025-63865-6

TY - JOUR

T1 - Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry

AU - Gheybi, Kazzem

AU - Soh, Pamela X. Y.

AU - Jiang, Jue

AU - Mbeki, Tumisang M. N.

AU - Louw, Melanie

AU - Burns, Daniel

AU - Mundra, Piyushkumar

AU - Kiriy, Daria

AU - Hasan, Md. Mehedi

AU - Jaratlerdsiri, Weerachai

AU - Lebelo, Maphuti Tebogo

AU - Campbell, Raymond A.

AU - Radzuma, Mulalo B.

AU - Nenzhelele, Mukudeni

AU - Obida, Muvhulawa

AU - Obida, Martin

AU - Ombuki, Winstar M.

AU - Oyaro, Micah O.

AU - Patrick, Sean M.

AU - Loda, Massimo

AU - Wedge, David C.

AU - Bristow, Robert G.

AU - Brewer, Daniel S.

AU - Cooper, Colin S.

AU - Reimand, Jüri

AU - Cancel-Tassin, Geraldine

AU - Cussenot, Olivier

AU - Hovens, Chris M.

AU - Cocoran, Niall M.

AU - Stricker, Phillip D.

AU - Schlomm, Thorsten

AU - Prins, Gail S.

AU - Sørensen, Karina Dalsgaard

AU - The Pan Prostate Cancer Group (PPCG)

AU - HEROIC PCaPH Africa1K

AU - Gihawi, Abraham

AU - Weischenfeldt, Joachim

AU - Mutambirwa, Shingai B. A.

AU - Ngugi, Peter M.

AU - Thomas, David M.

AU - Kote-Jarai, Zsofia

AU - Eeles, Rosalind A.

AU - Bornman, M. S. Riana

AU - Hayes, Vanessa M.

N1 - See the published article for information on data and code availability, and for funding information.

PY - 2025/10/2

Y1 - 2025/10/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=105017676226&partnerID=8YFLogxK

U2 - 10.1038/s41467-025-63865-6

DO - 10.1038/s41467-025-63865-6

M3 - Article

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 8799

ER -

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

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