TY - JOUR TI - Cancer therapy shapes the fitness landscape of clonal hematopoiesis AU - Bolton, Kelly L. AU - Ptashkin, Ryan N. AU - Gao, Teng AU - Braunstein, Lior AU - Devlin, Sean M. AU - Kelly, Daniel AU - Patel, Minal AU - Berthon, Antonin AU - Syed, Aijazuddin AU - Yabe, Mariko AU - Coombs, Catherine C. AU - Caltabellotta, Nicole M. AU - Walsh, Mike AU - Offit, Kenneth AU - Stadler, Zsofia AU - Mandelker, Diana AU - Schulman, Jessica AU - Patel, Akshar AU - Philip, John AU - Bernard, Elsa AU - Gundem, Gunes AU - Ossa, Juan E. Arango AU - Levine, Max AU - Martinez, Juan S. Medina AU - Farnoud, Noushin AU - Glodzik, Dominik AU - Li, Sonya AU - Robson, Mark E. AU - Lee, Choonsik AU - Pharoah, Paul D. P. AU - Stopsack, Konrad H. AU - Spitzer, Barbara AU - Mantha, Simon AU - Fagin, James AU - Boucai, Laura AU - Gibson, Christopher J. AU - Ebert, Benjamin L. AU - Young, Andrew L. AU - Druley, Todd AU - Takahashi, Koichi AU - Gillis, Nancy AU - Ball, Markus AU - Padron, Eric AU - Hyman, David M. AU - Baselga, Jose AU - Norton, Larry AU - Gardos, Stuart AU - Klimek, Virginia M. AU - Scher, Howard AU - Bajorin, Dean AU - Paraiso, Eder AU - Benayed, Ryma AU - Arcila, Maria E. AU - Ladanyi, Marc AU - Solit, David B. AU - Berger, Michael F. AU - Tallman, Martin AU - Garcia-Closas, Montserrat AU - Chatterjee, Nilanjan AU - Diaz, Luis A. AU - Levine, Ross L. AU - Morton, Lindsay M. AU - Zehir, Ahmet AU - Papaemmanuil, Elli T2 - Nature Genetics AB - 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. DA - 2020/10/26/ PY - 2020 DO - 10.1038/s41588-020-00710-0 DP - www.nature.com SP - 1 EP - 8 LA - en SN - 1546-1718 UR - https://www.nature.com/articles/s41588-020-00710-0 Y2 - 2020/10/26/17:29:16 ER -