Synapse - Cancer therapy shapes the fitness landscape of clonal hematopoiesis

Cancer therapy shapes the fitness landscape of clonal hematopoiesis Journal Article

Authors:	Bolton, K. L.; Ptashkin, R. N.; Gao, T.; Braunstein, L.; Devlin, S. M.; Kelly, D.; Patel, M.; Berthon, A.; Syed, A.; Yabe, M.; Coombs, C. C.; Caltabellotta, N. M.; Walsh, M.; Offit, K.; Stadler, Z.; Mandelker, D.; Schulman, J.; Patel, A.; Philip, J.; Bernard, E.; Gundem, G.; Arango Ossa, J. E.; Levine, M.; Medina Martinez, J. S.; Farnoud, N.; Glodzik, D.; Li, S.; Robson, M. E.; Lee, C.; Pharoah, P. D. P.; Stopsack, K. H.; Spitzer, B.; Mantha, S.; Fagin, J.; Boucai, L.; Gibson, C. J.; Ebert, B. L.; Young, A. L.; Druley, T.; Takahashi, K.; Gillis, N.; Ball, M.; Padron, E.; Hyman, D. M.; Baselga, J.; Norton, L.; Gardos, S.; Klimek, V. M.; Scher, H.; Bajorin, D.; Paraiso, E.; Benayed, R.; Arcila, M. E.; Ladanyi, M.; Solit, D. B.; Berger, M. F.; Tallman, M.; Garcia-Closas, M.; Chatterjee, N.; Diaz, L. A. Jr; Levine, R. L.; Morton, L. M.; Zehir, A.; Papaemmanuil, E.
Article Title:	Cancer therapy shapes the fitness landscape of clonal hematopoiesis
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. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Journal Title:	Nature Genetics
Volume:	52
Issue:	11
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Date Published:	2020-11-01
Start Page:	1219
End Page:	1226
Language:	English
DOI:	10.1038/s41588-020-00710-0
PUBMED:	33106634
PROVIDER:	scopus
PMCID:	PMC7891089
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85093941727&doi=10.1038%2fs41588-020-00710-0&partnerID=40&md5=8ca6d32e0ed1ef4335fd4129738ae067
Notes:	Article -- Export Date: 1 December 2020 -- Source: Scopus