The long-term effects of chemotherapy on normal blood cells

Emily Mitchell; My H Pham; Anna Clay; Rashesh Sanghvi; Nicholas Williams; Sandra Pietsch; Joanne I Hsu; Nina Friesgaard Øbro; Hyunchul Jung; Aditi Vedi; Sarah Moody; Jingwei Wang; Daniel Leonganmornlert; Michael Spencer Chapman; Ellie Dunstone; Anna Santarsieri; Alex Cagan; Heather E Machado; E Joanna Baxter; George Follows; Daniel J Hodson; Ultan McDermott; Gary J Doherty; Inigo Martincorena; Laura Humphreys; Krishnaa Mahbubani; Kourosh Saeb Parsy; Koichi Takahashi; Margaret A Goodell; David Kent; Elisa Laurenti; Peter J Campbell; Raheleh Rahbari; Jyoti Nangalia; Michael R Stratton

doi:10.1038/s41588-025-02234-x

The long-term effects of chemotherapy on normal blood cells

Emily Mitchell, My H Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I Hsu, Nina Friesgaard Øbro, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E Machado, E Joanna Baxter, George FollowsDaniel J Hodson, Ultan McDermott, Gary J Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A Goodell, David Kent, Elisa Laurenti, Peter J Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R Stratton

Afdeling for Klinisk Immunologi DIA

7 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	57
Udgave nummer	7
Sider (fra-til)	1684-1694
Antal sider	11
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-025-02234-x
Status	Udgivet - jul. 2025

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10.1038/s41588-025-02234-xLicens: CC BY

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Mitchell, E., Pham, M. H., Clay, A., Sanghvi, R., Williams, N., Pietsch, S., Hsu, J. I., Øbro, N. F., Jung, H., Vedi, A., Moody, S., Wang, J., Leonganmornlert, D., Spencer Chapman, M., Dunstone, E., Santarsieri, A., Cagan, A., Machado, H. E., Baxter, E. J., ... Stratton, M. R. (2025). The long-term effects of chemotherapy on normal blood cells. Nature Genetics, 57(7), 1684-1694. https://doi.org/10.1038/s41588-025-02234-x

Mitchell, E, Pham, MH, Clay, A, Sanghvi, R, Williams, N, Pietsch, S, Hsu, JI, Øbro, NF, Jung, H, Vedi, A, Moody, S, Wang, J, Leonganmornlert, D, Spencer Chapman, M, Dunstone, E, Santarsieri, A, Cagan, A, Machado, HE, Baxter, EJ, Follows, G, Hodson, DJ, McDermott, U, Doherty, GJ, Martincorena, I, Humphreys, L, Mahbubani, K, Saeb Parsy, K, Takahashi, K, Goodell, MA, Kent, D, Laurenti, E, Campbell, PJ, Rahbari, R, Nangalia, J & Stratton, MR 2025, 'The long-term effects of chemotherapy on normal blood cells', Nature Genetics, bind 57, nr. 7, s. 1684-1694. https://doi.org/10.1038/s41588-025-02234-x

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title = "The long-term effects of chemotherapy on normal blood cells",

abstract = "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.",

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AU - Clay, Anna

AU - Sanghvi, Rashesh

AU - Williams, Nicholas

AU - Pietsch, Sandra

AU - Hsu, Joanne I

AU - Øbro, Nina Friesgaard

AU - Jung, Hyunchul

AU - Vedi, Aditi

AU - Moody, Sarah

AU - Wang, Jingwei

AU - Leonganmornlert, Daniel

AU - Spencer Chapman, Michael

AU - Dunstone, Ellie

AU - Santarsieri, Anna

AU - Cagan, Alex

AU - Machado, Heather E

AU - Baxter, E Joanna

AU - Follows, George

AU - Hodson, Daniel J

AU - McDermott, Ultan

AU - Doherty, Gary J

AU - Martincorena, Inigo

AU - Humphreys, Laura

AU - Mahbubani, Krishnaa

AU - Saeb Parsy, Kourosh

AU - Takahashi, Koichi

AU - Goodell, Margaret A

AU - Kent, David

AU - Laurenti, Elisa

AU - Campbell, Peter J

AU - Rahbari, Raheleh

AU - Nangalia, Jyoti

AU - Stratton, Michael R

PY - 2025/7

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N2 - 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.

AB - 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.

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KW - Middle Aged

KW - Aged

KW - Adolescent

KW - Child

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KW - Child, Preschool

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KW - Male

KW - Female

KW - Mutation/drug effects

KW - Blood Cells/drug effects

KW - Antineoplastic Agents/adverse effects

KW - DNA Damage/drug effects

KW - Neoplasms/drug therapy

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VL - 57

SP - 1684

EP - 1694

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

The long-term effects of chemotherapy on normal blood cells

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