The long-term effects of chemotherapy on normal blood cells
Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3-80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes in the cell population structure of normal blood, similar to those caused by normal aging. The results show the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed as part of disease management, raising mechanistic questions and highlighting opportunities for the mitigation of adverse effects.
Authors
- Hyunchul Jung (ORCID: https://orcid.org/0000-0003-0450-2190)
- Heather E. Machado (ORCID: https://orcid.org/0000-0002-1523-3937)
- Daniel Leongamornlert (ORCID: https://orcid.org/0000-0002-3486-3168)
- Michael Spencer Chapman (ORCID: https://orcid.org/0000-0002-5320-8193)
- Aditi Vedi (ORCID: https://orcid.org/0000-0001-6761-6510)
- George Follows (ORCID: https://orcid.org/0000-0002-8489-0762)
- Laura Humphreys (ORCID: https://orcid.org/0009-0008-6697-8091)
- Alex Cagan (ORCID: https://orcid.org/0000-0002-7857-4771)
- Iñigo Martincorena (ORCID: https://orcid.org/0000-0003-1122-4416)
- Anna Santarsieri (ORCID: https://orcid.org/0000-0002-4449-2196)
- Krishnaa T. A. Mahbubani (ORCID: https://orcid.org/0000-0002-1327-2334)
- Peter J. Campbell (ORCID: https://orcid.org/0000-0002-3921-0510)
- Raheleh Rahbari (ORCID: https://orcid.org/0000-0002-1839-7785)
- David G. Kent (ORCID: https://orcid.org/0000-0001-7871-8811)
- Emily Mitchell (ORCID: https://orcid.org/0000-0002-2475-5737)
- My H. Pham (ORCID: https://orcid.org/0000-0002-0074-0733)
- Gary J. Doherty (ORCID: https://orcid.org/0000-0002-8158-8111)
- Kourosh Saeb‐Parsy (ORCID: https://orcid.org/0000-0002-0633-3696)
- E. Joanna Baxter (ORCID: https://orcid.org/0000-0002-5946-5238)
- Koichi Takahashi (ORCID: https://orcid.org/0000-0002-8027-9659)
- Michael R. Stratton (ORCID: https://orcid.org/0000-0001-6035-153X)
- Daniel J. Hodson (ORCID: https://orcid.org/0000-0001-6225-2033)
- Joanne I. Hsu (ORCID: https://orcid.org/0000-0002-1194-0650)
- Nicholas Williams (ORCID: https://orcid.org/0000-0003-3989-9167)
- Margaret A. Goodell (ORCID: https://orcid.org/0000-0003-1111-2932)
- Sandra Pietsch (ORCID: https://orcid.org/0000-0001-6398-253X)
- Ultan McDermott (ORCID: https://orcid.org/0000-0001-9032-4700)
- Rashesh Sanghvi (ORCID: https://orcid.org/0000-0002-7703-9216)
- Elisa Laurenti (ORCID: https://orcid.org/0000-0002-9917-9092)
- Jyoti Nangalia (ORCID: https://orcid.org/0000-0001-7122-4608)
- Ellie Dunstone
- Jingwei Wang (ORCID: https://orcid.org/0000-0002-0201-2369)
- Sarah Moody (ORCID: https://orcid.org/0000-0003-4904-1041)
- Anna Clay
Institutions
- AstraZeneca (United Kingdom) (GB)
- Babraham Institute (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Copenhagen University Hospital (DK)
- Rigshospitalet (DK)
- University of York (GB)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1038/s41588-025-02234-x
- Citations
- 21
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 19.66
Funders
- Wellcome
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Rosetrees Trust
- Blood Cancer UK
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre