1. Cancer therapy shapes the fitness landscape of clonal hematopoiesis
- Author
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David M. Hyman, Stuart Gardos, Gunes Gundem, Luis A. Diaz, James A. Fagin, Kelly L. Bolton, Catherine C. Coombs, Michael F. Berger, Nilanjan Chatterjee, Antonin Berthon, Nicole M. Caltabellotta, Konrad H. Stopsack, John Philip, Mariko Yabe, Barbara Spitzer, Virginia M. Klimek, Eder Paraiso, Max Levine, Ryan Ptashkin, Ahmet Zehir, Akshar Patel, Markus Ball, Zsofia K. Stadler, Juan E. Arango Ossa, Ross L. Levine, Lindsay M. Morton, Larry Norton, Lior Z. Braunstein, Minal Patel, Sean M. Devlin, Daniel Kelly, Noushin Farnoud, Mark E. Robson, Elsa Bernard, Laura Boucai, Maria E. Arcila, Kenneth Offit, Jessica Schulman, Montserrat Garcia-Closas, David B. Solit, Teng Gao, José Baselga, Ryma Benayed, Howard I. Scher, Simon Mantha, Martin S. Tallman, Elli Papaemmanuil, Andrew L. Young, Sonya Li, Dominik Glodzik, Nancy K. Gillis, Choonsik Lee, Juan S. Medina Martinez, Eric Padron, Benjamin L. Ebert, Marc Ladanyi, Michael Walsh, Aijazuddin Syed, Dean F. Bajorin, Paul D.P. Pharoah, Todd E. Druley, Koichi Takahashi, Christopher J. Gibson, Diana Mandelker, Philip, John [0000-0002-0535-7178], Bernard, Elsa [0000-0002-2057-7187], Levine, Max [0000-0001-5156-9086], Robson, Mark E [0000-0002-3109-1692], Pharoah, Paul DP [0000-0001-8494-732X], Stopsack, Konrad H [0000-0002-0722-1311], Fagin, James [0000-0002-2365-2517], Boucai, Laura [0000-0002-8852-1120], Ebert, Benjamin L [0000-0003-0197-5451], Takahashi, Koichi [0000-0002-8027-9659], Solit, David B [0000-0002-6614-802X], Garcia-Closas, Montserrat [0000-0003-1033-2650], Diaz, Luis A [0000-0002-7079-8914], Levine, Ross L [0000-0002-7884-1905], Zehir, Ahmet [0000-0001-5406-4104], Papaemmanuil, Elli [0000-0003-1709-8983], and Apollo - University of Cambridge Repository
- Subjects
Adult ,Male ,Myeloid ,Adolescent ,DNA damage ,Context (language use) ,Antineoplastic Agents ,Biology ,medicine.disease_cause ,Somatic evolution in cancer ,Models, Biological ,Clonal Evolution ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Neoplasms ,Genetics ,medicine ,Humans ,Selection, Genetic ,Child ,CHEK2 ,Gene ,030304 developmental biology ,Aged ,Aged, 80 and over ,0303 health sciences ,Mutation ,Infant, Newborn ,Cancer ,Infant ,Neoplasms, Second Primary ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Leukemia, Myeloid ,Child, Preschool ,Cancer research ,Female ,Genetic Fitness ,Clonal Hematopoiesis ,030217 neurology & neurosurgery - 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. 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.
- Published
- 2020