Prenatal Exposure to Chemotherapy Increases the Mutation Burden in Human Neonatal Hematopoietic Stem Cells

Chemotherapy is included in the standard-of-care for cancer treatment during pregnancy. However, whether prenatal exposure to maternal chemotherapy treatment has a mutagenic impact on the fetal genome remains unexplored. Therefore, we investigated mutation accumulation in hematopoietic stem and progenitor cells from neonates born to pregnant patients with cancer treated with chemotherapy, as well as healthy pregnant women and untreated pregnant patients with cancer. The mutational burden in hematopoietic stem and progenitor cells from neonates born to untreated pregnant patients with cancer and to healthy controls was similar but increased after prenatal exposure to varying types of chemotherapy regimens. Mutational signature analyses attributed the excess mutations to clock-like processes, which are active during normal cellular aging, or to direct mutagenesis by platinum-based drugs in neonates prenatally exposed to platinum-containing regimens. Our findings in the neonatal hematopoietic compartment are consistent with mutational signatures previously identified in cells of cancer survivors directly exposed to these chemotherapeutic drugs. Significance: This study demonstrates that environmental mutagenic exposure during pregnancy can increase somatic mutation accumulation in the fetus. Given that detrimental early life exposures can adversely affect health outcomes later in life, our study highlights the need for further research into the impact of environmentally induced genomic insults during the perinatal period.