Abstract 703: Epigenome-wide analysis of DNA methylation mediators linking cancer treatments to cardiometabolic risks in survivors of childhood cancer

Abstract Background: Cancer treatments engender the risk of long-term cardiometabolic and cardiac conditions among survivors of childhood cancer. However, the underlying biological mechanisms remain unclear. This study aimed to identify DNA methylation (DNAm) CpG sites associated with cardiometabolic risk factors (CMRFs) and adverse cardiac outcomes, and to assess if these DNAm CpG sites mediate associations between specific cancer treatments and these outcomes. Methods: We included 3, 044 survivors (median age at blood draw: 29.6 years) from the St. Jude Lifetime Cohort. Blood-derived DNA was profiled using the EPIC BeadChip. Associations between DNAm and seven clinically assessed outcomes were examined: five CMRFs (abnormal glucose metabolism, hypercholesterolemia, hypertriglyceridemia, hypertension, and obesity), and two cardiac outcomes (cardiomyopathy and myocardial infarction). Treatment-specific epigenome-wide association studies (EWAS) evaluated associations with 10 chemotherapeutic agents and four region-specific radiotherapies. Results: EWAS identified 1, 833 CpG sites associated with cardiometabolic outcomes (p < 9x10-8), including obesity (N=1, 709), abnormal glucose metabolism (N=141), and hypertriglyceridemia (N=134). A moderate number of CpG sites mapped to CPT1A, a key gene in fatty acid metabolism linked to metabolic disorders, with 23 outcome-CpG associations involving 7 unique CpG sites. Most (71%) outcome-associated CpG sites were also associated with cancer treatments, particularly chest- (N=610) and abdominal-radiotherapy (N=599), suggesting potential causal mediation for the treatment-related genotoxicity. Mediation analyses identified 386 CpG sites mediating treatment effects on cardiometabolic outcomes. Asparaginase treatment was significantly associated with abnormal glucose metabolism (Odds ratio [95% CI] = 1.09 [1.06-1.13]). Eighteen CpG sites collectively mediated 26.7% of this effect, with 14 previously implicated in type-2 diabetes. Similarly, alkylating agents were associated with hypertriglyceridemia (1.11 [1.07-1.14]) mediated by DNAm at 46 CpG sites; five independent CpG sites accounted for a substantial 79.8% of such mediation effect. Notably, 39 of these mediator CpG sites were previously associated with C-reactive protein (CRP) levels (two-sided Fisher’s test, p=2.2x10-30), suggesting potential DNAm-mediated inflammatory pathways connecting alkylating agents to triglyceride dysregulation. Conclusion: Our findings suggest that DNAm changes may mediate the association between cancer treatments and cardiometabolic risks. These results implicate inflammatory and metabolic pathways in treatment-related adverse outcomes. These insights may inform risk stratification and targeted interventions to improve cardiometabolic and cardiac health in childhood cancer survivors. Citation Format: Tiffany Eulalio, Yoonji Kim, Peggy Meng, Qian Dong, Noel-Marie Plonski, Heather Mulder, John Easton, Emily Walker, Geoffrey Neale, Deokumar Srivastava, Stephanie Dixon, Kirsten K. Ness, Melissa M. Hudson, Gregory T. Armstrong, Zhaoming Wang. Epigenome-wide analysis of DNA methylation mediators linking cancer treatments to cardiometabolic risks in survivors of childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 703.