Epigenetic Age Acceleration and Chronic Health Conditions Among Adult Survivors of Childhood Cancer

Abstract

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 2-sided.

Results: EAA was statistically significantly higher in survivors than controls (ALSM = 0.63, 95% confidence interval [CI] = 0.26 to 1.01 vs -3.61, 95% CI = -4.43 to 2.80). In a multivariable model among survivors, statistically significantly higher EAA (P < .05) was observed in those exposed to chest radiotherapy, abdomen or pelvic radiotherapy, alkylating agents, glucocorticoids, or epipodophyllotoxins. Compared with survivors with favorable health behaviors (ALSM = 0.26, 95% CI=-0.36 to 0.87), EAA was statistically significantly higher among survivors with intermediate (ALSM = 1.07, 95% CI = 0.59 to 1.54) or unfavorable health behaviors (ALSM = 1.45, 95% CI = 0.60 to 2.30). In time-to-event analyses, statistically significant associations were identified between EAA tertiles and incidence of 7 CHCs: hypertension (3rd vs 1st tertile, relative rate [RR] = 1.83, 95% CI = 1.17 to 2.83), myocardial infarction (RR = 2.91, 95% CI = 1.27 to 7.21), obesity (RR = 1.39, 95% CI = 1.17 to 1.66), obstructive pulmonary deficit (RR = 1.86, 95% CI = 0.95 to 3.77), peripheral motor neuropathy (RR = 2.89, 95% CI = 1.24 to 6.97), peripheral sensory neuropathy (RR = 2.04, 95% CI = 0.99 to 4.26), and pulmonary diffusion deficits (RR = 2.75, 95% CI = 0.95 to 7.63).

Conclusions: EAA is statistically significantly higher in survivors of childhood cancer than in noncancer controls and is associated with specific treatment exposures, unfavorable health behaviors, and presence of specific CHCs.

Figure 1.

Linear regression lines of epigenetic age by age at DNA sampling for survivors and controls.

Figure 2.

Adjusted least square mean (ALSM) of epigenetic age acceleration (EAA) in controls and survivors overall and across primary cancer diagnoses. P values refer to the statistical significance of differences in ALSM of EAA between survivors (overall and by diagnosis) and controls. Detailed estimates are provided in the Supplementary Table 1 (available online). Statistical significance for pairwise comparisons of ALSM of EAA among primary cancer diagnosis groups is provided in the Supplementary Table 2 (available online). ALL = acute lymphoblastic leukemia; CNS = central nervous system; HL = Hodgkin lymphoma; NBL = neuroblastoma; NHL = non-Hodgkin lymphoma; WT = Wilms tumor.

Figure 3.

Adjusted least square mean (ALSM) of epigenetic age acceleration (EAA) among survivors by cancer treatments in a multivariable model. Detailed estimates are provided in the Supplementary Table 5 (available online). RT = radiotherapy.

Figure 4.

Adjusted least square mean (ALSM) of epigenetic age acceleration (EAA) among survivors (A) and noncancer controls (B) by groups of health behaviors. Detailed estimated are provided in the Supplementary Table 6 (available online).

Figure 5.

Dynamics of epigenetic age and telomere length differs between individuals with no history of cancer and survivors of childhood cancer due to exposures to chemotherapy and/or radiation therapy.