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

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.
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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.
Authors
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.
Loda, M.
Wedge, D. C.
Bristow, R. G.
Brewer, D. S.
Cooper, C. S.
Reimand, J.
Cancel-Tassin, G.
Cussenot, O.
Hovens, C. M.
Cocoran, N. M.
Stricker, P. D.
Schlomm, T.
Prins, G. S.
Sørensen, K. D.
Weischenfeldt, J.
Mutambirwa, S. B. A.
Ngugi, P. M.
Thomas, D. M.
Kote-Jarai, Z.
Eeles, R. A.
Bornman, M. S. R.
Hayes, V. M.
Affiliation
Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia. School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa. National Health Laboratory Services, Johannesburg, South Africa. Department of Anatomical Pathology, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. The Institute of Cancer Research, London, UK. Childrens Cancer Institute, Lowy Cancer Centre, University of New South Wales Sydney, Randwick, NSW, Australia. Biotech Research & Innovation Centre & Finsen Laboratory, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. Computational Genomics Group, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia. Department of Physiology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa. Department of Urology, University of Pretoria, Pretoria, South Africa. Department of Urology, Sefako Makgatho Health Science University, Dr George Mukhari Academic Hospital, Medunsa, Ga-Rankuwa, South Africa. Tshilidzini Hospital, Shayandima, Thohoyandou, Limpopo, South Africa. Department of Urology, East African Kidney Institute, University of Nairobi, Nairobi, Kenya. Department of Human Pathology, University of Nairobi, Nairobi, Kenya. Department of Pathology and Laboratory Medicine, Weil Cornell Medicine, New York, NY, USA. Manchester Cancer Research Centre, University of Manchester, Manchester, M20 4GJ, UK. Norwich Medical School, University of East Anglia, Norwich, UK. The Earlham Institute, Norwich Research Park, Norwich, UK. Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada. Department of Medical Biophysics & Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. CeRePP, Hospital Tenon, Paris, France. Sorbonne Universite, GRC n°5 Predictive Onco-Urology, APHP, Tenon Hospital, Paris, France. Collaborative Center for Genomic Cancer Medicine University of Melbourne, The Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia. Department of urology, Royal Melbourne Hospital, Melbourne, Parkville, VIC, Australia. Department of Surgery, The University of Melbourne, Parkville, VIC, Australia. St Vincent's Prostate Cancer Research Centre, Sydney, NSW, Australia. Charité Universitätsmedizin Berlin, Berlin, Germany. Department of Urology, University of Illinois at Chicago, Chicago, IL, 60612, USA. Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark. Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark. Centre for Molecular Oncology, School of Biomedical Sciences, University of New South Wales Sydney, Randwick, NSW, Australia. The Royal Marsden NHS Foundation Trust London, London, UK. Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia. vanessa.hayes@sydney.edu.au. School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa. vanessa.hayes@sydney.edu.au. Manchester Cancer Research Centre, University of Manchester, Manchester, M20 4GJ, UK. vanessa.hayes@sydney.edu.au. Norwich Medical School, University of East Anglia, Norwich, UK. vanessa.hayes@sydney.edu.au.
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2025
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All Paterson Institute for Cancer Research
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Gheybi K, Soh PXY, Jiang J, Mbeki TMN, Louw M, Burns D, et al. Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry. Nature communications. 2025 Oct 2;16(1):8799. PubMed PMID: 41038821. Pubmed Central PMCID: PMC12491615 R.A.E.). Member of external expert committee to Astra Zeneca UK (R.A.E.). Honoraria from GU-ASCO, Janssen, University of Chicago, Dana Farber Cancer Institute USA as a speaker (R.A.E.). Educational honorarium from Bayer and Ipsen (R.A.E.). Member of the SAB of Our Future Health (R.A.E.). Undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK (R.A.E.). The remaining authors declare no competing interests. Epub 2025/10/03. eng.
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https://christie.openrepository.com/handle/10541/627961
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