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.

Description

Acknowledgements: This work was delivered as part of the Mutographs team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (CRUK) (C98/A24032). This work was supported by Wellcome grants 206194 and 220540/Z/20/A and by the NIHR Cambridge Biomedical Research Centre (BRC-1215-555 20014). J.N. was supported by CRUK, Alborda Trust, Rosetrees Trust, Blood Cancer UK and Wellcome. D.J.H. was supported by a fellowship from CRUK (RCCFEL\100072) and received core funding from the CRUK Cambridge Centre (A25117). E.L. was supported by a Wellcome–Royal Society Sir Henry Dale Fellowship (107630/Z/15/Z). E.L. and D.J.H. were supported by core support grants from Wellcome and the Medical Research Council (MRC) to the Wellcome–MRC Cambridge Stem Cell Institute (203151/Z/16/Z). Samples were provided by the Cambridge Blood and Stem Cell Biobank, which is supported by the NIHR Cambridge BRC, Wellcome Trust–MRC Stem Cell Institute and the Cambridge Experimental Cancer Medicine Centre, UK. This research was supported by the NIHR Cambridge BRC Cell Phenotyping Hub. We are grateful to the donors, donor families and the Cambridge Biorepository for Translational Medicine for the gift of their tissue. We would like to thank L. O’Neill, K. Roberts, K. Smith, S. Austin-Guest and the staff of DNA Pipelines at the Wellcome Sanger Institute for their contributions. For the purpose of open access, we have applied a CC BY public copyright license to any author-accepted paper version arising from this submission. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440

Keywords

31 Biological Sciences, 3102 Bioinformatics and Computational Biology, 3105 Genetics, Cancer, Genetics, Aging, 2.1 Biological and endogenous factors, 6.1 Pharmaceuticals, 1.1 Normal biological development and functioning, Cancer, Generic health relevance

Journal Title

Nature Genetics

Journal ISSN

1061-4036
1546-1718

Volume Title

57

Publisher

Springer Science and Business Media LLC

Publisher DOI

https://doi.org/10.1038/s41588-025-02234-x

Rights and licensing

Except where otherwised noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/

Sponsorship

Wellcome Trust (107630/Z/15/Z)
Wellcome Trust (203151/Z/16/Z)
Cancer Research UK (RCCFEL\100072)

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