P-127: Gestational diabetes mellitus and pediatric cancer risk: converging epigenetic, metabolic, and inflammatory pathways

Abstract

Gestational diabetes mellitus (GDM) not only alters the intrauterine environment but has also been linked to a higher risk of childhood cancer. Understanding the biological mechanisms behind this association is essential for developing preventive strategies for at-risk children. We aimed to integrate current knowledge on the main molecular pathways connecting maternal GDM to pediatric malignancies, with a focus on epigenetic changes, hyperglycemia, and hyperinsulinemia. A comprehensive narrative review of published studies was performed. We gathered and synthesized evidence from cell biology, epigenetics, and signaling pathway analyses to identify converging mechanisms that drive cancer susceptibility. GDM-driven epigenetic dysregulation silences critical tumor suppressors (TP53, BRCA1, CDKN2A) and activates oncogenes (MYC, IGF2) through PI3K/AKT/mTOR and Wnt pathways. At the same time, maternal hyperglycemia fuels NF-κB-mediated inflammation, TGF-β-dependent epithelial-mesenchymal transition, and oxidative stress. Concurrent hyperinsulinemia enhances insulin/IGF-1 signaling, IL-17-related inflammation, and GPER/HIF-1α crosstalk. Importantly, several of these pathways have a dual role, being capable of both stimulating and restraining tumor formation depending on the cellular context. Intertwined epigenetic, metabolic, and inflammatory disturbances caused by maternal GDM create a pro-oncogenic fetal milieu. These findings offer a mechanistic basis for identifying risk biomarkers and designing early protective interventions, reinforcing the importance of optimal glucose control during pregnancy for the lifelong health of the child.