Impact of Chemotherapy on the Somatic Mutation Burden of Sperm and Other Tissues

Many chemotherapeutic agents impair cancer growth by inducing DNA damage. The impact of these agents on mutagenesis in normal cells, including sperm, is largely unknown. Here, we applied high-fidelity duplex sequencing to 94 samples from 36 individuals exposed to diverse chemotherapies and 32 controls. We found that many of the sperm samples from men exposed to chemotherapy, the somatic mutation burden was elevated as compared to controls and the expected burden based on trio studies. We then validated this finding using other tissues, also finding an increased somatic mutation burden in the blood and liver of many subjects exposed to chemotherapy as compared to unexposed controls. Similarly, mice treated with three cycles of cisplatin had an increased somatic mutation burden in sperm but also in the liver, and hematopoietic progenitor cells. These results suggest an association between cancer therapies and somatic mutation burden.