TY - JOUR
T1 - Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry
AU - HEROIC PCaPH Africa1K
AU - Pan Prostate Cancer Group
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 - Zanettini, Claudio
AU - Yamaguchi, Takafumi N.
AU - Xu, Yaobo
AU - Uhrig, Sebastian
AU - Soh, Pamela X.Y.
AU - Sahli, Atef
AU - Robinson, Brain
AU - Reimand, Jüri
AU - Rausch, Tobias
AU - Queiroz, Lucio R.
AU - Pope, Bernard
AU - Pellegrina, Diogo
AU - Papenfuss, Anthony T.
AU - Molania, Ramyar
AU - Marchionni, Luigi
AU - Lutsik, Pavlo
AU - Leeman, Gregory
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
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 - https://www.scopus.com/pages/publications/105017676226
U2 - 10.1038/s41467-025-63865-6
DO - 10.1038/s41467-025-63865-6
M3 - Article
C2 - 41038821
AN - SCOPUS:105017676226
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 8799
ER -
