Epigenome-wide analysis identifies DNA methylation mediators of treatment-related cardiometabolic risk in survivors of childhood cancer

Childhood cancer survivors face increased cardiometabolic risks from cancer treatment exposures, yet mechanisms remain unclear. Here, epigenome-wide analysis identifies 1893 DNA methylation (DNAm) sites in peripheral-blood-mononuclear-cells (PBMCs) associated with at least one cardiometabolic risk factor (CMRF), including obesity (n = 1720), abnormal glucose (n = 201), hypertriglyceridemia (n = 145), hypercholesterolemia (n = 38) and hypertension (n = 34) in 2938 survivors from the St. Jude Lifetime Cohort. A core set of five DNAm sites near CPT1A and LMNA is associated with all CMRFs. Mediation analyses identify 24 sites mediating associations between treatments and CMRFs, implicating inflammatory and metabolic pathways. Notably, cg20370568, a cis-expression quantitative trait methylation site for ANTXR2, mediates 20% of the effect of body-trunk-radiotherapy on abnormal glucose. These findings suggest that prior genotoxic cancer treatments may become biologically embedded through DNAm variations that could contribute to cardiometabolic dysfunction and highlight candidate biomarkers for refining risk stratification and guiding intervention strategies in survivorship care. The mechanisms underlying increased cardiometabolic risk from cancer treatment in childhood cancer survivors remain to be explored. Here, epigenome-wide analysis in childhood cancer survivors identified DNA methylation sites that mediate treatment-related cardiometabolic risks and are associated with inflammatory and metabolic pathways.