Cancer therapy shapes the fitness landscape of clonal hematopoiesis

• Published in: Nature genetics Vol. 52; no. 11; pp. 1219 - 1226
• Main Authors: Bolton, Kelly L., Ptashkin, Ryan N., Gao, Teng, Braunstein, Lior, Devlin, Sean M., Kelly, Daniel, Patel, Minal, Berthon, Antonin, Syed, Aijazuddin, Yabe, Mariko, Coombs, Catherine C., Caltabellotta, Nicole M., Walsh, Mike, Offit, Kenneth, Stadler, Zsofia, Mandelker, Diana, Schulman, Jessica, Patel, Akshar, Philip, John, Bernard, Elsa, Gundem, Gunes, Ossa, Juan E. Arango, Levine, Max, Martinez, Juan S. Medina, Farnoud, Noushin, Glodzik, Dominik, Li, Sonya, Robson, Mark E., Lee, Choonsik, Pharoah, Paul D. P., Stopsack, Konrad H., Spitzer, Barbara, Mantha, Simon, Fagin, James, Boucai, Laura, Gibson, Christopher J., Ebert, Benjamin L., Young, Andrew L., Druley, Todd, Takahashi, Koichi, Gillis, Nancy, Ball, Markus, Padron, Eric, Hyman, David M., Baselga, Jose, Norton, Larry, Gardos, Stuart, Klimek, Virginia M., Scher, Howard, Bajorin, Dean, Paraiso, Eder, Benayed, Ryma, Arcila, Maria E., Ladanyi, Marc, Solit, David B., Berger, Michael F., Tallman, Martin, Garcia-Closas, Montserrat, Chatterjee, Nilanjan, Diaz, Luis A., Levine, Ross L., Morton, Lindsay M., Zehir, Ahmet, Papaemmanuil, Elli
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2020; Nature Publishing Group
• Subjects: 45; 45/23; 631/114; 631/208/212; 692/699/67/1990; Adolescent; Adult; Aged; Aged, 80 and over; Agriculture; Animal Genetics and Genomics; Antineoplastic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cancer therapies; Care and treatment; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - radiation effects; Child; Child, Preschool; Clonal Evolution; Clonal Hematopoiesis - drug effects; Clonal Hematopoiesis - genetics; Cohort Studies; Damage; Deoxyribonucleic acid; Diagnosis; DNA; DNA damage; DNA topoisomerase (ATP-hydrolysing); Endometrial cancer; Female; Gene Function; Gene mutations; Genetic aspects; Genetic Fitness; Health aspects; Hematopoiesis; Human Genetics; Humans; Infant; Infant, Newborn; Leukemia, Myeloid - genetics; Male; Middle Aged; Models, Biological; Mutation; Myelocytic leukemia; Neoplasia; Neoplasms; Neoplasms - drug therapy; Neoplasms - radiotherapy; Neoplasms, Second Primary - genetics; Nonlymphoid leukemia; Oncology, Experimental; Ovarian cancer; p53 Protein; Platinum; Risk factors; Selection, Genetic; Sequential sampling; Smoking; Therapy; Young Adult; United States
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-020-00710-0

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.