Therapy-Related Clonal Hematopoiesis in Patients With Non-hematologic Cancers Is Common and Associated With Adverse Clinical Outcomes

Cell Stem Cell. 2017 Sep 7;21(3):374-382.e4. doi: 10.1016/j.stem.2017.07.010. Epub 2017 Aug 10.

Abstract

Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use. PPM1D and TP53 mutations were associated with prior exposure to chemotherapy. CH and CH-PD led to an increased incidence of subsequent hematologic cancers, and CH-PD was associated with shorter patient survival. These data suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology.

Keywords: biological sciences; cancer; cancer genomics; diseases; genetics; health sciences; hematological cancer; hematological diseases; mutation.

Publication types

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

MeSH terms

  • Aged
  • Clone Cells
  • Cohort Studies
  • Female
  • Genetic Association Studies
  • Hematologic Neoplasms / genetics
  • Hematologic Neoplasms / pathology*
  • Hematologic Neoplasms / therapy*
  • Hematopoiesis*
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Risk Factors
  • Survival Analysis
  • Treatment Outcome