Cancer therapy shapes the fitness landscape of clonal hematopoiesis
Open accessAbstract
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.
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Environmental factors and exposure to certain substances can significantly alter clonal composition, promoting positive selection and accelerating the physiological restriction of the stem cell pool.
“While aging plays a critical role in driving these changes, it is well established that environmental factors and exposure to certain substances can significantly alter clonal composition promoting positive selection and accelerating the physiological restriction of the stem cell pool. 25-27”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [25]
The Main section, “Clinical parameters shape the fitness landscape of CH” (page unavailable), says that cancer treatment, smoking, and aging affect the relative fitness of hematopoietic clones in a gene-dependent manner. The “Clonal dynamics” section reports that cancer therapy selects for particular clones. Our copy does not establish that these exposures accelerate the physiological restriction of the stem cell pool. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAging plays a critical role in driving changes in clonal composition.
“While aging plays a critical role in driving these changes, it is well established that environmental factors and exposure to certain substances can significantly alter clonal composition promoting positive selection and accelerating the physiological restriction of the stem cell pool. 25-27”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [25]
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- 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., Ossa, J. E. A., Levine, M., Martinez, J. S. M., 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., Levine, R. L., Morton, L. M., Zehir, A., & Papaemmanuil, E.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of North Carolina at Chapel Hill (US)
- National Institutes of Health (US)
- University of Cambridge (GB)
- Dana-Farber Cancer Institute (US)
- Washington University in St. Louis (US)
- The University of Texas MD Anderson Cancer Center (US)
- Moffitt Cancer Center (US)
- University of Cologne (DE)
- AstraZeneca (United Kingdom) (GB)
- Johns Hopkins University (US)
- Corresponding author
- Zehir, Ahmet
- Papaemmanuil, Elli
- ORCID
- Bolton, Kelly L.
- Ptashkin, Ryan N.
- Gao, Teng
- Braunstein, Lior
- Devlin, Sean M.
- Kelly, Daniel
- Syed, Aijazuddin
- Yabe, Mariko
- Coombs, Catherine C.
- Caltabellotta, Nicole M.
- Offit, Kenneth
- Stadler, Zsofia
- Mandelker, Diana
- Schulman, Jessica
- Philip, John
- Bernard, Elsa
- Gundem, Gunes
- Levine, Max
- Farnoud, Noushin
- Robson, Mark E.
- Lee, Choonsik
- Pharoah, Paul D. P.
- Stopsack, Konrad H.
- Spitzer, Barbara
- Mantha, Simon
- Fagin, James
- Boucai, Laura
- Gibson, Christopher J.
- Ebert, Benjamin L.
- Young, Andrew L.
- Druley, Todd
- Takahashi, Koichi
- Gillis, Nancy
- Ball, Markus
- Padron, Eric
- Hyman, David M.
- Baselga, Jose
- Norton, Larry
- Gardos, Stuart
- Scher, Howard
- Bajorin, Dean
- Paraiso, Eder
- Benayed, Ryma
- Arcila, Maria E.
- Ladanyi, Marc
- Solit, David B.
- Berger, Michael F.
- Tallman, Martin
- Garcia-Closas, Montserrat
- Chatterjee, Nilanjan
- Diaz, Luis A.
- Levine, Ross L.
- Morton, Lindsay M.
- Zehir, Ahmet
- Papaemmanuil, Elli
- Venue
- Nature Genetics
- Published
- 2020-10-26
- Volume
- 52
- Issue
- 11
- Pages
- 1219-1226
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC7891089
- OpenAlex
- W3093490071
- Cited by
- 751
- References
- 14
- Citations by year
- 2026: 101 · 2025: 145 · 2024: 133 · 2023: 151 · 2022: 137 · 2021: 76 · 2020: 8
- FWCI
- 58.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- European Hematology Association
- Gabrielle’s Angel Foundation for Cancer Research
- V Foundation for Cancer Research
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (K08 CA241318)
- American Society of Hematology
- Edward P. Evans Foundation
- Starr Cancer Consortium
- U.S. Department of Health & Human Services | National Institutes of Health (P50 CA172012, K12 CA120780, UG1 HL069315)
- Conquer Cancer Foundation
- U.S. Department of Defense (W81XWH-18-1-0330)
- Cycle for Survival
- EIF | Stand Up To Cancer (SU2C-AACR-DT22-17)
- 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, therapy-related myeloid neoplasms, fitness landscape, clonal selection, ASXL1 mutation, DNA damage response genes, TP53, PPM1D, CHEK2, radiation exposure, topoisomerase II inhibitors, environmental exposure, clonal evolution, cancer risk prediction, clinical sequencing
- MeSH terms
- Clonal Hematopoiesis, Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Cell Transformation, Neoplastic, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Leukemia, Myeloid, Male, Middle Aged, Models, Biological, Mutation, Neoplasms, Selection, Genetic, Cohort Studies, Neoplasms, Second Primary, Young Adult, Genetic Fitness, Clonal Evolution
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