Cancer therapy shapes the fitness landscape of clonal hematopoiesis

Nat Genet. 2020 Nov;52(11):1219-1226. doi: 10.1038/s41588-020-00710-0. Epub 2020 Oct 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology
  • 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
  • Female
  • Genetic Fitness
  • Humans
  • Infant
  • Infant, Newborn
  • Leukemia, Myeloid / genetics
  • Male
  • Middle Aged
  • Models, Biological
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / radiotherapy
  • Neoplasms, Second Primary / genetics*
  • Selection, Genetic
  • Young Adult


  • Antineoplastic Agents