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 Leongamornlert, 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, Iñigo Martincorena, Laura Humphreys, Krishnaa T. Mahbubani, Kourosh Saeb‐Parsy, Koichi Takahashi, Margaret A. Goodell, David G. Kent, Elisa Laurenti, Peter J. Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R. Stratton
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.