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<p>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.</p>

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Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月15日

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  • 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

摘要

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.