Open AccessCancer therapy shapes the fitness landscape of clonal hematopoiesis
Author(s) -
Kelly L. Bolton,
Ryan Ptashkin,
Teng Gao,
Lior Z. Braunstein,
Sean M. Devlin,
Daniel Kelly,
Minal Patel,
Antonin Berthon,
Aijazuddin Syed,
Mariko Yabe,
Catherine C. Coombs,
Nicole M. Caltabellotta,
Meghara Walsh,
Kenneth Offit,
Zsofia K. Stadler,
Diana Mandelker,
Jessica Schulman,
Akshar Patel,
John Philip,
Elsa Bernard,
Gunes Gundem,
Juan Arango Ossa,
Max F. Levine,
Juan Martínez,
Noushin Farnoud,
Dominik Glodzik,
Sonya Li,
Mark E. Robson,
Choonsik Lee,
Paul D.P. Pharoah,
Konrad H. Stopsack,
Barbara Spitzer,
Simon Mantha,
James A. Fagin,
Laura Boucai,
Christopher J. Gibson,
Benjamin L. Ebert,
Andrew L. Young,
Todd E. Druley,
Koichi Takahashi,
Nancy Gillis,
Markus Ball,
Eric Padron,
David M. Hyman,
J. Baselga,
Larry Norton,
Stuart M. Gardos,
Virginia M. Klimek,
Howard I. Scher,
Dean F. Bajorin,
Eder Paraiso,
Ryma Benayed,
Maria E. Arcila,
Marc Ladanyi,
David B. Solit,
Michael F. Berger,
Martin S. Tallman,
Montserrat García-Closas,
Nilanjan Chatterjee,
Luis A. Díaz,
Ross L. Levine,
Lindsay M. Morton,
Ahmet Zehir,
Elli Papaemmanuil
Publication year - 2020
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-020-00710-0
Subject(s) - biology , context (archaeology) , cancer , mutation , haematopoiesis , genetics , somatic evolution in cancer , gene , cancer research , stem cell , paleontology
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.