Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy
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 K. Griffin, Benjamin L. Ebert, Taralynn Mack, Yash Pershad, Brian Sharber, Michael F. Berger, Ahmet Zehir, Ryan Ptashkin, Ross L. Levine, Elli Papaemmanuil, Joseph Vijai, 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
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. The relationship between pathogenic germline variation, clonal hematopoiesis (CH) and risk of hematologic malignancy is explored in 731,835 individuals across 6 cohorts. Carriers of variants in certain genes show distinct patterns of CH and increased risk of CH progression to malignancy.