Prenatal exposure to chemotherapy increases the mutation burden in human neonatal hematopoietic stem cells
Ilana Struys, Carolina Velázquez, Joske Ubels, Charlotte L. LeJeune, Markus J. van Roosmalen, Axel K.M. Rosendahl Huber, Anais J.C.N. van Leeuwen, Wouter Bossuyt, Bernard Thienpont, Thierry Voet, Kristel Van Calsteren, Liesbeth Lenaerts, Ruben van Boxtel, Frédéric AmantAbstract
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 (HSPCs) from neonates born to pregnant cancer patients treated with chemotherapy, as well as healthy pregnant women and untreated pregnant cancer patients. The mutational burden in HSPCs from neonates born to untreated pregnant cancer patients 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.