Epigenetic age acceleration and chronic health conditions among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort

Abstract

Background: The epigenetic clock becomes an important biomarker in aging research, where epigenetic age (EA) approximates chronological age with high accuracy and epigenetic age acceleration (EAA) demonstrates superior performance in predicting health outcomes in the general population. The utility of EAA among adult survivors of childhood cancer is largely unknown. We aimed to compare EAA between childhood cancer survivors and non-cancer controls, and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs) among survivors.

Methods: Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood derived DNA from 2139 survivors and 282 community controls with no prior history of cancer. EAA was estimated as the residual value from the fit of a simple linear regression of EA (using Levine's clock) on chronological age (i.e., age at DNA sampling). Cumulative doses of chemotherapy and region-specific radiation exposures were abstracted from medical records. Health behaviors including physical activity, diet, tobacco smoking, and alcohol consumption were assessed from questionnaires and categorized as favorable, intermediate and unfavorable. Multivariable piecewise-exponential regression model was employed to evaluate associations of EAA with 59 clinically assessed CHCs.

Results: EA was highly correlated with chronological age with the same Pearson coefficient (r = 0.88) in survivors and controls; however, EAA was significantly higher in survivors than controls, overall (adjusted least square mean [ALSM] = 0.63 vs. -3.61 years, P<0.001) and across primary diagnoses (ranging from ALSM = -1.27 in central nervous system tumor to 4.61 in Hodgkin lymphoma). Among survivors, significantly higher EAA was associated with exposures to chest RT, abdomen/pelvic RT, alkylating agents, glucocorticoids, or epipodophyllotoxins. Compared to survivors with favorable health behaviors (ALSM = 0.26), EAA was higher in survivors with intermediate (1.07, P = 0.04) or unfavorable health behaviors (1.45, P = 0.03). After adjusting for attained age, sex, age at diagnosis, and treatment, significant linear trends across tertiles of EAA were identified in associations with occurrences of five CHCs: hypertension (Relative Rate = 1.83 for survivors with EAA in the 3rd vs. the 1st tertile, 95% CI = 1.17-2.83); myocardial infraction (2.91, 1.27-7.21); obesity (1.39, 1.17-1.66); obstructive pulmonary deficit (1.86, 0.95-3.77); and peripheral sensory neuropathy (2.04, 0.99-4.26).

Conclusion: EAA is significantly higher in childhood cancer survivors than non-cancer controls and is associated with treatment exposures, health behaviors, and CHCs. Clinically, EAA may inform intervention strategies including health coaching to prevent or delay the onset of CHCs among survivors of childhood cancer.