Abstract 7488: Prenatal exposure to chemotherapy increases the mutation burden in human neonatal hematopoietic stem cells

Abstract Background. Nowadays, chemotherapy is included in the standard of care for cancer treatment during pregnancy, and is considered clinically safe for the child’s cognitive, cardiac and brain development up until early adolescence. However, whether prenatal exposure to maternal chemotherapy treatment has a mutagenic impact on the fetal genome, remains unexplored. Patients and methods. We investigated mutation accumulation in hematopoietic stem and progenitor cells (HSPCs) from neonates born to pregnant cancer patients treated with chemotherapy (n=13), as well as healthy pregnant women (n=9) and untreated pregnant cancer patients (n=4). From every subject, cord blood, as a source for neonatal DNA, was collected at delivery, whereafter single HSPCs were isolated and clonally expanded for subsequent whole-genome sequencing (15ξ). Signature analyses was performed using the MutationalPatterns R package and comparison with the COSMIC database. Results. The mutational burden identified in HSPCs from neonates born to untreated pregnant cancer patients and to healthy controls was similar (mean of single base substitutions (SBS)=41.2±9.1 and 39.9±14.3 respectively; p=0.97) and reflected the expected mutation burden from healthy individuals at birth. In contrast, HSPCs from neonates prenatally exposed to varying chemotherapy regimens, showed an increased number of somatic mutations (mean SBS=89.7±59.2; p=0.0038). Mutational signature analyses attributed the excess mutations to either clock-like processes, which are active during normal cellular aging, or to direct mutagenesis by platinum-based drugs in the case of neonates prenatally exposed to platinum-containing regimens. Our findings in early neonatal tissue are consistent with mutational signatures previously identified in healthy cells of cancer survivors directly exposed to chemotherapeutic drugs and are validated via direct in vitro exposure of cord blood HSPCs from healthy individuals to single chemotherapeutic agents frequently used to treat pregnant women. Conclusion. 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 environmental maternal exposures associated to genomic insults during the perinatal period. Citation Format: Ilana Struys, Carolina Velázquez, Joske Ubels, Charlotte L. LeJeune, Markus van Roosmalen, Axel Rosendahl Huber, Anaïs van Leeuwen, Wouter Bossuyt, Bernard Thienpont, Thierry Voet, Kristel Van Calsteren, Liesbeth Lenaerts, Ruben van Boxtel, Frédéric Amant. Prenatal exposure to chemotherapy increases the mutation burden in human neonatal hematopoietic stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7488.