种系遗传变异影响克隆造血景观和恶性肿瘤的进展，这一成果由美国华盛顿大学Kelly L. Bolton课题组经过不懈努力而取得。相关论文于2025年7月15日发表于国际顶尖学术期刊《自然—遗传学》杂志上。

本文研究了731835例个体生殖系遗传变异对克隆造血（CH）的影响。研究组发现了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。

研究人员表示，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。

附：英文原文

Title: Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy

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

Issue&Volume: 2025-07-15

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.

DOI: 10.1038/s41588-025-02250-x

Source: https://www.nature.com/articles/s41588-025-02250-x