Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy

IF 31.7 1区生物学 Q1 GENETICS & HEREDITY

Nature genetics Pub Date : 2025-07-15 DOI:10.1038/s41588-025-02250-x

Jie Liu, Duc Tran, Liying Xue, Brian J. Wiley, Caitlyn Vlasschaert, Caroline J. Watson, Hamish A. J. MacGregor, Xiaoyu Zong, Irenaeus C. C. Chan, Indraniel Das, Md Mesbah Uddin, Abhishek Niroula, Gabriel Griffin, Benjamin L. Ebert, Taralynn Mack, Yash Pershad, Brian Sharber, Michael Berger, Ahmet Zehir, Ryan Ptashkin, Ross L. Levine, Elli Papaemmanuil, Vijai Joseph, Teng Gao, Yelena Kemel, Diana Mandelker, Konrad H. Stopsack, Paul D. P. Pharoah, Semanti Mukherjee, Li Ding, Yin Cao, Matthew J. Walter, Jamie R. Blundell, Nilanjan Chatterjee, Kenneth Offit, Lucy A. Godley, Daniel C. Link, Zsofia K. Stadler, Alexander G. Bick, Pradeep Natarajan, Kelly L. Bolton

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Abstract

With age, clonal expansions occur pervasively across normal tissues yet only in rare instances lead to cancer, despite being driven by well-established cancer drivers. Characterization of the factors that influence clonal progression is needed to inform interventional approaches. Germline genetic variation influences cancer risk and shapes tumor mutational profile, but its influence on the mutational landscape of normal tissues is not well known. Here we studied the impact of germline genetic variation on clonal hematopoiesis (CH) in 731,835 individuals. We identified 22 new CH-predisposition genes, most of which predispose to CH driven by specific mutational events. CH-predisposition genes contribute to unique somatic landscapes, reflecting the influence of germline genetic backdrop on gene-specific CH fitness. Correspondingly, somatic–germline interactions influence the risk of CH progression to hematologic malignancies. These results demonstrate that germline genetic variation influences somatic evolution in the blood, findings that likely extend to other tissues.

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种系遗传变异影响克隆造血景观和恶性肿瘤的进展

随着年龄的增长，克隆扩增在正常组织中普遍发生，但只有在极少数情况下导致癌症，尽管它是由公认的癌症驱动因素驱动的。需要确定影响克隆进展的因素，以便为介入治疗提供信息。种系遗传变异影响癌症风险和形成肿瘤突变谱，但其对正常组织突变谱的影响尚不清楚。本文研究了731,835例个体生殖系遗传变异对克隆造血（CH）的影响。我们发现了22个新的CH易感基因，其中大多数易感基因是由特定的突变事件驱动的。CH易感基因促成了独特的体细胞景观，反映了种系遗传背景对基因特异性CH适应度的影响。相应地，体细胞与生殖系的相互作用影响CH进展为血液系统恶性肿瘤的风险。这些结果表明，种系遗传变异影响血液中的体细胞进化，这一发现可能延伸到其他组织。

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 genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution