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 A. Mundra, Daria Kiriy, Md Mehedi Hasan, Weerachai Jaratlerdsiri, Maphuti Tebogo Lebelo, Raymond Campbell, Mulalo B. Radzuma, Mukudeni Nenzhelele, Muvhulawa Obida, Martin Obida, Winstar Mokua Ombuki, Micah Oyaro, Sean M. Patrick, Massimo Loda, David C. Wedge, Robert G. Bristow, Daniel S. Brewer, Colin S. Cooper, Jüri Reimand, Géraldine Cancel‐Tassin, Olivier Cussenot, Christopher M. Hovens, Niall M. Cocoran, Phillip D. Stricker, Thorsten Schlomm, Gail S. Prins, Karina D. Sørensen, Pan Prostate Cancer Group, G. Steven Bova, Mark N. Brook, Benedikt Brors, Adam P. Butler, Kevin Cheng, Niall M. Corcoran, Francesco Favero, Clarissa Gerhäuser, Abraham Gihawi, Etsehiwot G. Girma, Vincent J. Gnanapragasam, Andreas Gruber, Anis Hamid, Vanessa M. Hayes, Housheng Hansen He, Eddie L. Imada, G. Maria Jakobsdottir, Weerachai Jaratlersiri, Jue Jiang, Chol-Hee Jung, Francesca Khani, Philippe Lamy, Gregory Leeman, Pavlo Lutsik, Luigi Marchionni, Ramyar Molania, Anthony T. Papenfuss, Diogo Pellegrina, Bernard J. Pope, Lúcio Queiroz, Tobias Rausch, Jüri Reimand, Brain Robinson, Atef Sahli, Pamela X. Y. Soh, Sebastian Uhrig, Yaobo Xu, Takafumi N. Yamaguchi, Claudio Zanettini, HEROIC PCaPH Africa1K, M. S. Riana Bornman, P M Ngugi, Winstar Mokua Ombuki, Sean M. Patrick, Daniel M. Moreira, Ikenna Madueke, Maria Argos, I.E.J. Barnhoorn, Lynn Birch, Jenna Craddock, Giuseppe Fanelli, Eva F. Jensby, Hagen E. A. Förtsch, Jessie Gamxamub, Kazzem Gheybi, Abraham Gihawi, Tingting Gong, Md Mehedi Hasan, Vivien Holmes, Ruotian Huang, Zsofia Kote‐Jarai, Maphuti Tebogo Lebelo, Pavlo Lutsik, Umuna Maendo, Tumisang M. N. Mbeki, Reginald Menoe
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.