Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes
Open accessAbstract
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.
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D-2-hydroxyglutarate (D2HG) inhibits numerous demethylases, leading to changes in genomic and transcriptomic methylation profiles as well as gene expression and genome topology.
“D-2-hydroxyglutarate (D2HG) is one such oncometabolite, which inhibits numerous demethylases, leading to changes in genomic and transcriptomic methylation profiles as well as gene expression and genome topology 32,90-92 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [91]
One study found that CHIP mutations were more prevalent in patients treated for solid cancers than in populations not selected for cancer.
“One study of a patient population treated for solid cancers found that CHIP mutations were more prevalent in this group than in populations not selected for cancer 77.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [77]
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- Authors
- Coombs, C. C., Zehir, A., Devlin, S. M., Kishtagari, A., Syed, A., Jonsson, P., Hyman, D. M., Solit, D. B., Robson, M. E., Baselga, J., Arcila, M. E., Ladanyi, M., Tallman, M. S., Levine, R. L., & Berger, M. F.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Levine, Ross L.
- Berger, Michael F.
- ORCID
- Venue
- Cell stem cell
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 21
- Issue
- 3
- Pages
- 374-382.e4
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC5591073
- OpenAlex
- W2745259295
- Cited by
- 866
- References
- 39
- Citations by year
- 2026: 76 · 2025: 105 · 2024: 105 · 2023: 115 · 2022: 139 · 2021: 76 · 2020: 105 · 2019: 81 · 2018: 54 · 2017: 8
- FWCI
- 52.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH National Cancer Institute (P30 CA008748)
- Conquer Cancer Foundation American Society of Clinical Oncology Young Investigator Award
- Stand Up to Cancer Convergence Program
- National Science Foundation (NSF/SU2C 2015-003)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Epidemiology › Multiple and Secondary Primary Cancers
- Keywords
- clonal hematopoiesis, PPM1D mutation, TP53 mutation, survival outcomes, radiotherapy, chemotherapy, tobacco use, aging, somatic mutations
- MeSH terms
- Aged, Clone Cells, Female, Hematopoiesis, Humans, Male, Middle Aged, Mutation, Risk Factors, Cohort Studies, Survival Analysis, Treatment Outcome, Hematologic Neoplasms, Genetic Association Studies
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