Background: We have previously reported that epigenetic age acceleration (EAA) was associated with prior cancer treatment exposures and certain chronic health conditions (CHCs) among adult survivors of childhood cancer, but the early epigenetic aging pattern among children and adolescent survivors and its implication in CHCs, especially early-onset CHCs, remain to be explored. Methods: Expanded DNAm profiling with EPIC array for survivors in the St. Jude Lifetime Cohort covered the age <20 years (n=690 in a total of 2,846). Epigenetic age (EA) was measured with four epigenetic clocks, i.e., Horvath, Hannum, Levine, and GrimAge. The annual change of EA and EAA were compared in 5 different chronological age groups, i.e., children (0-9 years), adolescent (10-19 years), young adults (20-34 years), middle-aged adults (35-49 years, and old adults (≥50). Logistic regression evaluated the association between EAA and early-onset obesity (<20 years) or severity/burden score of all CHCs. Cox regression assessed the association between EAA and late-mortality. Results: The annual mean change in EA using Horvath and Levine clocks was greatest in children (2.18; 1.63 years) and steadily decreased across age groups with the lowest change in adults ≥50 years (0.53; 0.76 years). However, Hannum and GrimAge clocks showed the greatest annual mean change in young adults (0.76; 0.80 years). Moreover, the Horvath and Levine clocks showed lower EAA in children (-3.57; -0.22) and older adults (-2.34; -1.70) and higher in adolescents (0.92; 1.32) and young adults (1.10; 1.46). Levine and GrimAge clock EAA was significantly associated with increased risk of developing early-onset obesity (Odds Ratio [OR]=1.05, 95% CI=1.01-1.08, p<0.01; OR=1.12, 95% CI=1.03-1.12, p=0.01), increased severity and burden of CHCs (OR=1.02, 95% CI=1.01-1.04, p=0.02; OR=1.04, 95% CI=1.00-1.07, p=0.05)) and late mortality (Hazard Ratio [HR]=1.10, 95% CI=1.05-1.15, p<0.001; HR=1.17, 95% CI=1.10-1.26, p<0.001). Conclusions: Our investigation showed the EAA measured in children and adolescent survivors may be predictive of early-onset CHCs, severity/burden of all CHCs was well as early morality, highlighting that the early start of accelerated aging warrants a need for earlier intervention to prevent morbidity and mortality later in life in childhood cancer survivors. Children and adolescents at elevated aging “trajectory” might benefit greatly from earlier anti-aging interventions including non-pharmacologic (e.g., lifestyle modifications) and pharmacologic (e.g., DNA methylation/demethylating agents) strategies. Citation Format: Noel-Marie Plonski, Cheng Chen, Qian Dong, Na Qin, Kyla C. Shelton, Emily Finch, John Easton, Heather Mulder, Jinghui Zhang, Geoffrey Neale, Emily Walker, Hui Wang, Kevin Krull, Kirsten K. Ness, Melissa M Hudson, Leslie L. Robinson, Qian Li, AnnaLynn Williams, Zhaoming Wang. Epigenetic age in peripheral blood among children, adolescent, and adult survivors of childhood cancer [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B017.

ImportanceCertain cancer therapies are risk factors for epigenetic age acceleration (EAA) among survivors of childhood cancer, and EAA is associated with chronic health conditions (CHCs). However, small numbers of younger survivors (aged <20 years) previously evaluated have limited the ability to calculate EAA among this age group.ObjectiveTo evaluate the change rate of epigenetic age (EA) and EAA in younger compared with older survivors and the possible association of EAA with early-onset obesity (aged <20 years), severity/burden of CHCs, and late mortality (>5 years from cancer diagnosis).Design, Setting, and ParticipantsStudy participants were from the St Jude Lifetime Cohort, initiated in 2007 with ongoing follow-up. The present study was conducted from April 17, 2022, to March 23, 2023. Survivors in this cohort of European ancestry with DNA methylation data were included. Cross-sectional annual changes in EA and EAA were compared across 5 different chronologic age groups: age 0 to 9 (children), 10 to 19 (adolescents), 20 to 34 (younger adults), 35 to 49 (middle-aged adults), and greater than or equal to 50 (older adults) years. Logistic regression evaluated the association between EAA and early-onset obesity or severity/burden of CHCs. Cox proportional hazards regression assessed the association between EAA and late mortality.Main Outcomes and MeasuresEarly-onset obesity, severity/burden of CHCs (graded using the Common Terminology Criteria for Adverse Events (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life-threatening) and were combined into high vs low severity/burden based on frequency and grade), and late mortality were the outcomes based on follow-up until April 2020. Expanded DNA methylation profiling increased the number of survivors younger than 20 years (n = 690). Epigenetic age was calculated primarily using the Levine clock, and EAA was derived from least squares regression of EA against chronologic age and was standardized to a z score (Levine EEA).ResultsAmong 2846 participants (median age, 30.3 [IQR, 9.3-41.5] years; 53% males), the cross-sectional annual change in EA_Levine was higher in children (1.63 years) and adolescents (1.14 years), and the adjusted least-squares mean of Levine EEA was lower in children (−0.22 years) and older adults (−1.70 years). Each 1-SD increase in Levine EEA was associated with increased risk of developing early-onset obesity (odds ratio [OR], 1.46; 95% CI, 1.19-1.78), high severity/burden of CHCs (OR, 1.13; 95% CI, 1.03-1.24), and late mortality (hazard ratio, 1.75; 95% CI, 1.35-2.26).Conclusions and RelevanceThe findings of this study suggest that EAA measured in children and adolescent survivors of childhood cancer is associated with early-onset obesity, severity/burden of all CHCs, and late mortality. Evaluating EAA may help identify survivors of childhood cancer at increased risk for early-onset obesity, morbidity in general, and mortality.

Background DNA methylation (DNAm) plays an important role in lipid metabolism, however, no epigenome-wide association study (EWAS) of lipid levels has been conducted among childhood cancer survivors. Here, we performed EWAS analysis with longitudinally collected blood lipid data from survivors in the St. Jude lifetime cohort study. Methods Among 2052 childhood cancer survivors of European ancestry (EA) and 370 survivors of African ancestry (AA), four types of blood lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG), were measured during follow-up beyond 5-years from childhood cancer diagnosis. For the exposure EWAS (i.e., lipids measured before blood draw for DNAm), the DNAm level was an outcome variable and each of the blood lipid level was an exposure variable; vice versa for the outcome EWAS (i.e., lipids measured after blood draw for DNAm). Results Among EA survivors, we identified 43 lipid-associated CpGs in the HDL (n = 7), TC (n = 3), and TG (n = 33) exposure EWAS, and 106 lipid-associated CpGs in the HDL (n = 5), LDL (n = 3), TC (n = 4), and TG (n = 94) outcome EWAS. Among AA survivors, we identified 15 lipid-associated CpGs in TG exposure (n = 6), HDL (n = 1), LDL (n = 1), TG (n = 5) and TC (n = 2) outcome EWAS with epigenome-wide significance (P < 9 × 10−8). There were no overlapping lipids-associated CpGs between exposure and outcome EWAS among EA and AA survivors, suggesting that the DNAm changes of different CpGs could be the cause or consequence of blood lipid levels. In the meta-EWAS, 12 additional CpGs reached epigenome-wide significance. Notably, 32 out of 74 lipid-associated CpGs showed substantial heterogeneity (Phet < 0.1 or I2 > 70%) between EA and AA survivors, highlighting differences in DNAm markers of blood lipids between populations with diverse genetic ancestry. Ten lipid-associated CpGs were cis-expression quantitative trait methylation with their DNAm levels associated with the expression of corresponding genes, out of which seven were negatively associated. Conclusions We identified distinct signatures of DNAm for blood lipids as exposures or outcomes and between EA and AA survivors, revealing additional genes involved in lipid metabolism and potential novel targets for controlling blood lipids in childhood cancer survivors.

Our published studies demonstrated that epigenetic age acceleration (EAA) is significantly higher in childhood cancer survivors than non-cancer controls. Additionally, EAA is associated with germline genetics, cancer treatments, unfavorable health behaviors, and chronic health conditions. However, our previous studies were limited to non-Hispanic whites (NHW). We aimed to investigate and compare the EAA between non-Hispanic blacks (NHB) and NHW, and evaluate the contribution of social determinants of health (SDOH) to potential racial disparity in EAA. Methylation profiling was generated using Infinium EPIC BeadChips on blood derived DNA from 460 NHB and 2,052 NHW from the St. Jude Lifetime Cohort. EAA was estimated as the residual from the fit of a simple linear regression of epigenetic age (EA, using Levine’s clock) on chronological age (CA, i.e., age at DNA sampling). Cumulative doses of chemotherapy and region-specific radiation exposures were abstracted from medical records. Educational attainment was categorized into 3 levels (&lt; high school, high school, ≥ college). Personal income was categorized into 3 levels (none, &lt; $40,000 and ≥ $40,000). For socioeconomic area deprivation index (ADI), we considered &gt;75th percentile, 40th to 75th percentile, and &lt;40th percentile as high, moderate, and low deprivation, respectively. Multivariable linear regression evaluated associations of EAA with race and SDOH adjusting for sex and cancer treatments. Mediation analysis treated SDOH as mediators, EAA as an outcome, and race as an exposure. The Pearson r between EA and CA was 0.85 and 0.58, and the age slope of EA (i.e., annual change rate of EA) was 1.21 and 0.91, for NHW and NHB, respectively. EAA was much higher in NHB (mean, 5.31; sd, 7.21) than NHW (mean, -1.19; sd, 12.48) with significance in a multivariable regression model adjusting for sex and cancer treatment (NHB vs. NHW: β = 1.90, P = 9.24×10-5). EAA was also associated with educational attainment (high school vs. &lt;high school: β = -2.84, P = 3.22×10-5; college vs. &lt;high school: β = -3.75, P = 2.03×10-7) and ADI (moderate vs. low: β= 1.07, P = 0.026; high vs. low: β = 1.58, P = 2.26×10-3), but not personal income. Notably, after adjusting for SDOH, the association between EAA and race was moderately attenuated (β = 1.50, P = 8.37×10-3). Both educational attainment (15.5%) and ADI (21.4%) mediated the association between race and EAA. We found racial disparity in EAA, with both personal and geographic SDOH as mediators of the association between race and EAA. These data indicate that changes in the social support system at both a personal and community level are needed to reduce socioeconomic disadvantage (e.g., lower education and poor living conditions) and hence the biological aging trajectory. In addition, moderate correlation between EA and CA among NHB suggests that further refined measurement of EA for NHB survivors is needed. Citation Format: Noel-Marie Plonski, Cheng Chen, Qian Dong, Na Qin, Nan Song, John Easton, Heather Mulder, Emily Walker, Geoffrey Neale, Jinghui Zhang, Kevin Krull, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, I-Chan Huang, Zhaoming Wang. Racial disparity and roles of social determinants of health in epigenetic age acceleration among survivors of childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3503.