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

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-10-02 DOI:10.1038/s41467-025-63865-6

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, 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

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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.

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致病变异揭示了非洲血统男性前列腺癌生殖系检测的候选基因。

前列腺癌（PCa）生殖系检测，虽然获得势头，是血统限制和非洲独家。通过对217例非洲祖先病例（186例南部非洲人，31例Pan代表）的全基因组测序，我们确定了78个DNA损伤修复或PCa相关基因中的172个潜在致病变异。报告的（13/217,5.99%）和累积预测的（24/217,11.06%）显著变异（11个基因）的患病率低于非非洲人的报告。相反，BRCA1、HOXB13、CDK12、MLH1、MSH2和BRIP1不受影响。通过基于变异频率和功能、临床表现和肿瘤匹配双等位基因失活的致病性排序，排名靠前的候选基因包括PREX2、POLE、FAT1、BRCA2、POLQ、LRP1B和ATM。除了DNA聚合酶（包括POLG）的显著影响外，范可尼贫血基因包括FANCD2、FANCA、FANCG、ERCC4、FANCE和FANCI，而DNA错配修复基因MSH3和PMS1的排名高于已知的同类基因MSH6和PMS2。这项研究提供了对非洲相关的潜在致病性PCa变异谱的见解，突出了急需的基因候选基因，用于包括祖先的种系检测。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.