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

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; S&#248;rensen, KD; Weischenfeldt, J; Mutambirwa, SBA; Ngugi, PM; Thomas, DM; Kote-Jarai, Z; Eeles, RA; Bornman, MSR; Hayes, VM

Author(s): 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; Weischenfeldt, J; Mutambirwa, SBA; Ngugi, PM; Thomas, DM; Kote-Jarai, Z; Eeles, RA; Bornman, MSR; Hayes, VM;
Details: Publication Year 2025-10-02,Volume 16,Issue #1,Page 8799
Journal Title: Nature Communications
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.
Publisher: Springer Nature
Keywords: Humans; Male; *Prostatic Neoplasms/genetics/ethnology; *Germ-Line Mutation; *Black People/genetics; *Genetic Predisposition to Disease; Genetic Testing; Whole Genome Sequencing; Middle Aged; DNA Repair/genetics
Research Division(s): Bioinformatics and Computational Biology
Publisher's Version: https://doi.org/10.1038/s41467-025-63865-6
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-63865-6
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-12-05 09:07:33

Last Modified: 2025-12-05 09:29:13