Scholarlink

<p>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, <i>BRCA1</i>, <i>HOXB13, CDK12, MLH1, MSH2</i>, and <i>BRIP1</i> remain unimpacted. Through pathogenic ranking based on variant frequency and functionality, clinical presentation and tumour-matched biallelic inactivation, top-ranked candidates include <i>PREX2, POLE, FAT1, BRCA2, POLQ, LRP1B</i> and <i>ATM</i>. Besides notable impact of DNA polymerases, including <i>POLG</i>, Fanconi anaemia genes include <i>FANCD2</i>, <i>FANCA, FANCG, ERCC4, FANCE</i> and <i>FANCI</i>, while DNA mismatch repair genes <i>MSH3</i> and <i>PMS1</i> outranked known namesakes <i>MSH6</i> and <i>PMS2</i>. This study provides insights into the spectrum of African-relevant potentially pathogenic PCa variants, highlighting much-needed gene candidates for ancestry-inclusive germline testing.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月2日

查看全文
  • Kazzem Gheybi,
  • Pamela X. Y. Soh,
  • Jue Jiang,
  • Tumisang M. N. Mbeki,
  • Melanie Louw,
  • Daniel Burns,
  • Piyushkumar Mundra,
  • Daria Kiriy,
  • Md. Mehedi Hasan,
  • Weerachai Jaratlerdsiri,
  • Maphuti Tebogo Lebelo,
  • Raymond A. Campbell,
  • Mulalo B. Radzuma,
  • Mukudeni Nenzhelele,
  • Muvhulawa Obida,
  • Martin Obida,
  • Winstar M. Ombuki,
  • Micah O. Oyaro,
  • Sean M. Patrick,
  • Massimo Loda,
  • David C. Wedge,
  • Robert G. Bristow,
  • Daniel S. Brewer,
  • Colin S. Cooper,
  • Jüri Reimand,
  • 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,
  • Benedict Brors,
  • Adam Butler,
  • Kevin C. L. Cheng,
  • Niall M. Corcoran,
  • Francesco Favero,
  • Clarissa Gerhauser,
  • Abraham Gihawi,
  • Etsehiwot G. Girma,
  • Vincent J. Gnanapragasam,
  • Andreas J. Gruber,
  • Anis Hamid,
  • Vanessa M. Hayes,
  • Housheng Hansen He,
  • Eddie Luidy 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 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,
  • M. S. Riana Bornman,
  • 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,
  • Zsofia Kote-Jarai,
  • 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,
  • Rosalind A. Eeles,
  • M. S. Riana Bornman,
  • Vanessa M. Hayes

摘要

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.