Cancer therapy shapes the fitness landscape of clonal hematopoiesis

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1219-1226
Number of pages8
JournalNature Genetics
Volume52
Issue number11
DOIs
StatePublished - Nov 1 2020

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