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Cancer therapy shapes the fitness landscape of clonal hematopoiesis

2020; Nature Portfolio; Volume: 52; Issue: 11 Linguagem: Inglês

10.1038/s41588-020-00710-0

1546-1718

Kelly L. Bolton, Ryan Ptashkin, Teng Gao, Lior Z. Braunstein, Sean M. Devlin, Daniel J. Kelly, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine C. Coombs, Nicole M. Caltabellotta, Mike Walsh, Kenneth Offit, Zsofia K. Stadler, Diana Mandelker, Jessica Schulman, Akshar Patel, John Philip, Elsa Bernard, Gunes Gundem, Juan Arango Ossa, Max F. Levine, Juan Martínez, Noushin Farnoud, Dominik Głodzik, Sonya Li, Mark E. Robson, Choonsik Lee, Paul D.P. Pharoah, Konrad H. Stopsack, Barbara Spitzer, Simon Mantha, James A. Fagin, Laura Boucai, Christopher J. Gibson, Benjamin L. Ebert, Andrew L. Young, Todd E. Druley, Koichi Takahashi, Nancy Gillis, Markus Ball, Eric Padron, David M. Hyman, José Baselga, Larry Norton, Stuart M. Gardos, Virginia M. Klimek, Howard I. Scher, Dean F. Bajorin, Eder Paraiso, Ryma Benayed, Maria E. Arcila, Marc Ladanyi, David B. Solit, Michael F. Berger, Martin S. Tallman, Montserrat García‐Closas, Nilanjan Chatterjee, Luis A. Díaz, Ross L. Levine, Lindsay M. Morton, Ahmet Zehir, Elli Papaemmanuil,

Hematopoietic Stem Cell Transplantation

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies. Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.