Epigenetic Age in Peripheral Blood Among Children, Adolescent, and Adult Survivors of Childhood Cancer

Abstract 36
Importance: We previously demonstrated that some cancer therapies are strong risk factors for 37 epigenetic age acceleration (EAA) among childhood cancer survivors, and EAA is associated with chronic 38 health conditions (CHCs). However, these data included few survivors that were <20 years old, limiting 39 the ability to calculate early epigenetic aging. 40
Objective: We aimed to evaluate the annual mean change rate of epigenetic age and EAA in children 41 and adolescent survivors and compare to survivors with older chronological age, and further associated 42 EAA with early-onset obesity, severity/burden of all CHCs and late-mortality. 43
Design, Setting and Participants: A total of 2,846 survivors of European ancestry from the St. Jude 44 Lifetime Cohort (SJLIFE) was included in the analysis. Annual change in EA and EAA were compared in 5 45 different chronological age groups, i.e., 0-9 (children), 10-19 (adolescent), 20-34 (young adults), 35-49 46 (middle aged adults), and >50 (old adults) years. Logistic regression evaluated the association between 47 EAA and early-onset obesity (<20 years of age) or severity/burden score of CHCs. Cox regression 48 assessed the association between EAA and late-mortality. 49
Main Outcomes and Measures: Early-onset obesity, severity/burden of all CHCs and late-mortality 50 based on current SJLIFE data freeze were the outcomes. Expanded DNAm profiling increased the 51 number of survivors aged <20 years (690 of 2,846). Epigenetic age (EA) was calculated for four 52 epigenetic clocks, i.e., Horvath, Hannum, Levine, and GrimAge. 53
Results: The annual mean change in EA_Horvath or EA_Levine was higher in children (2.18; 1.63, years) 54 and adolescents (0.80; 1.14, years), and the mean EAA_Horvath or EAA_Levine was lower in children (-55 3.57; -0.22, years) and older adults (-2.34; -1.70, years). EAA_Levine or EAA_GrimAge was significantly 56 associated with risk in developing early-onset obesity (odds ratio [OR], 1.05; 95%CI, 1.01-1.08; OR, 1.12; 57 95%CI, 1.03-1.21), severity/burden of CHCs (OR, 1.02; 95%CI, 1.00-1.04; OR, 1.03; 95% CI, 1.00-1.04) and 58 late-mortality (hazard ratio [HR], 1.10; 95%CI, 1.05-1.15, HR, 1.17; 95% CI, 1.10-1.26). 59
4
Conclusion and Relevance: EAA measured in children and adolescent survivors was associated with 60 early-onset obesity, severity/burden of all CHCs and late-mortality. Evaluating EAA may help identify 61 survivors at increased risk for early-onset obesity, morbidity in general as well as mortality.