LAUSR

BACKGROUND Mounting evidence supports the occurrence of accelerating aging among long-term survivors of childhood cancer. We aimed to investigate epigenetic age acceleration (EAA) in survivors and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs). METHODS Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood-derived DNA from 2139 survivors and 282 frequency matched controls from the St. Jude Lifetime Cohort Study. EAAs were estimated as residuals from a linear regression of epigenetic age (Levine's clock) against chronological age. Adjusted least square mean (ALSM) of EAA was calculated and compared between survivors and controls, across treatment exposures and health behaviors. Associations of EAA with 20 clinically-assessed CHCs were evaluated with multivariable piecewise-exponential models. All statistical tests for P values below were two-sided. RESULTS EAA was statistically significantly higher in survivors than controls (ALSM=0.63, 95%CI=0.26-1.01 vs. -3.61, 95%CI=-4.43-2.80). In a multivariable model among survivors, statistically significantly higher EAA (P<0.05) was observed in those exposed to chest-radiotherapy (RT), abdomen/pelvic-RT, alkylating agents, glucocorticoids or epipodophyllotoxins. Compared to survivors with favorable health behaviors (0.26, 95%CI=-0.36-0.87), EAA was statistically significantly higher among survivors with intermediate (1.07, 95%CI=0.59-1.54) or unfavorable health behaviors (1.45, 95%CI=0.60-2.30). In time-to-event analyses, statistically significant associations were identified between EAA tertiles and incidence of seven CHCs: hypertension (3rd vs. 1st tertile, Relative Rate [RR]=1.83, 95%CI=1.17-2.83), myocardial infarction (RR = 2.91, 95%CI=1.27-7.21), obesity (RR = 1.39, 95%CI=1.17-1.66), obstructive pulmonary deficit (RR = 1.86, 95%CI=0.95-3.77), peripheral motor neuropathy (RR = 2.89, 95%CI=1.24-6.97), peripheral sensory neuropathy (RR = 2.04, 95%CI=0.99-4.26), and pulmonary diffusion deficits (RR = 2.75, 95%CI=0.95-7.63). CONCLUSIONS EAA is statistically significantly higher in survivors of childhood cancer than in non-cancer controls and is associated with specific treatment exposures, unfavorable health behaviors, and presence of specific CHCs.