Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry
Abstract
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.
Article Details
Authors (103)
Melanie Louw
Daniel Burns
Piyushkumar Mundra
Daria Kiriy
Weerachai Jaratlerdsiri
Raymond A. Campbell
Mulalo B. Radzuma
Mukudeni Nenzhelele
Muvhulawa Obida
Martin Obida
Micah O. Oyaro
Massimo Loda
David C. Wedge
Robert G. Bristow
Daniel S. Brewer
Colin S. Cooper
Geraldine Cancel-Tassin
Olivier Cussenot
Chris M. Hovens
Niall M. Cocoran
Phillip D. Stricker
Thorsten Schlomm
Gail S. Prins
Karina Dalsgaard Sørensen
G. Steven S. Bova
Mark N. Brook
Institute of Cancer Research, London
Benedict Brors
Adam Butler
Kevin C. L. Cheng
Niall M. Corcoran
Francesco Favero
Clarissa Gerhäuser
Etsehiwot G. Girma
Vincent J. Gnanapragasam
Department of Urology, Cambridge University Hospitals National Health Service Foundation Trust
Andreas J. Gruber
Anis Hamid
Housheng Hansen He
Eddie Luidy Imada
G. Maria Jakobsdottir
Weerachai Jaratlersiri
Jue jiang
Chol-Hee Jung
Francesca Khani
Philippe Lamy
Gregory Leeman
Luigi Marchionni
Ramyar Molania
Anthony T. Papenfuss
Diogo Pellegrina
Bernard Pope
Lucio R. Queiroz
Tobias Rausch
Jüri Reimand
Brain Robinson
Atef Sahli
Pamela X. Y. Soh
Sebastian Uhrig
Yaobo Xu
Takafumi N. Yamaguchi
Claudio Zanettini
Peter Mungai Ngugi
Winstar M. Ombuki
Sean M. Patrick
Daniel M. Moreira
Ikenna C. Madueke
Maria Argos
Irene E. J. Barnhoorn
Lynn Birch
Jenna Craddock
G. Nicolo’ Fanelli
Eva Ferlev Jensby
Hagen E. A. Förtsch
Jessie Gamxamub
Kazzem Gheybi
Abraham Gihawi
Tingting Gong
Md. Mehedi Hasan
Vivien Holmes
Ruotian Huang
Maphuti Tebogo Lebelo
Pavlo Lutsik
Umuna Maendo
Tumisang M. N. Mbeki
Reginald Menoe
Muriuki Elias Nyaga
Willis Oyieko
Joyce Shirinde
Golda Stellmacher
Avraam Tapinos
Korawich Uthayopas
Douglas I. Walker
Edwin O. O. Walong
Githui Sheila Wanjiku
Allan Yienya
Kangping Zhou
Joachim Weischenfeldt
Shingai B. A. Mutambirwa
Peter M. Ngugi
David M. Thomas
Zsofia Kote-Jarai
Institute of Cancer Research, London
Rosalind A. Eeles
Institute of Cancer Research, London
M. S. Riana Bornman
Vanessa M. Hayes