Genetic background influences susceptibility to chemotherapy-induced hematotoxicity

Abstract

Hematotoxicity is a life-threatening side effect of many chemotherapy regimens. Although clinical factors influence patient responses, genetic factors may also play an important role. We sought to identify genomic loci that influence chemotherapy-induced hematotoxicity by dosing Diversity Outbred mice with one of three chemotherapy drugs; doxorubicin, cyclophosphamide or docetaxel. We observed that each drug had a distinct effect on both the changes in blood cell subpopulations and the underlying genetic architecture of hematotoxicity. For doxorubicin, we mapped the change in cell counts before and after dosing and found that alleles of ATP-binding cassette B1B (Abcb1b) on chromosome 5 influence all cell populations. For cyclophosphamide and docetaxel, we found that each cell population was influenced by distinct loci, none of which overlapped between drugs. These results suggest that susceptibility to chemotherapy-induced hematotoxicity is influenced by different genes for different chemotherapy drugs.

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Acknowledgements

This work was funded by the National Cancer Institute grant number RC1 CA14550402. We thank Annika Bohner for her excellent technical assistance and Sara Cassidy for technical editing.

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Correspondence to G A Churchill.

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DMG and GAC are employed by The Jackson Laboratory, which sells Diversity Outbred mice.

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Gatti, D., Weber, S., Goodwin, N. et al. Genetic background influences susceptibility to chemotherapy-induced hematotoxicity. Pharmacogenomics J 18, 319–330 (2018). https://doi.org/10.1038/tpj.2017.23

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