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

Author

Listed:
  • 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
    University of the Witwatersrand)

  • 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
    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
    Shayandima)

  • Martin Obida

    (University of Pretoria
    Shayandima)

  • 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
    Norwich Research Park)

  • Colin S. Cooper

    (The Institute of Cancer Research
    University of East Anglia)

  • Jüri Reimand

    (Ontario Institute for Cancer Research
    University of Toronto)

  • Geraldine Cancel-Tassin

    (Hospital Tenon
    Tenon Hospital)

  • Olivier Cussenot

    (Hospital Tenon
    Tenon Hospital)

  • Chris M. Hovens

    (The Victorian Comprehensive Cancer Centre
    Melbourne
    The University of Melbourne)

  • Niall M. Cocoran

    (The Victorian Comprehensive Cancer Centre
    Melbourne
    The University of Melbourne)

  • 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
    Aarhus University)

  • Joachim Weischenfeldt

    (University of Copenhagen
    Charité Universitätsmedizin Berlin)

  • 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
    The Royal Marsden NHS Foundation Trust London)

  • M. S. Riana Bornman

    (University of Pretoria)

  • Vanessa M. Hayes

    (University of Sydney
    University of Pretoria
    University of Manchester
    University of East Anglia)

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.

Suggested Citation

  • 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 Lebel, 2025. "Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63865-6
    DOI: 10.1038/s41467-025-63865-6
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