Cancer Treatment–Related Cardiotoxicity among Survivors of Childhood Cancer: A Comparative and Integrated View of Multiple Measures of Biological Age Acceleration

Abstract Background: We conducted a comparative and integrated analysis of biological age acceleration (BioAgeAccel) to improve understanding of cancer treatment–related cardiotoxicity among childhood cancer survivors. Methods: Treatment-related cardiotoxicity was exemplified by two cardiovascular diseases (CVD): cardiomyopathy and myocardial infarction (MI). DNA methylation (DNAm) profiles of peripheral blood mononuclear cells in the St. Jude Lifetime Cohort were generated using Illumina EPIC BeadChips. BioAgeAccel was assessed with 43 DNAm-based biomarkers. Multivariable logistic regression evaluated associations between BioAgeAccel and cardiotoxicity and assessed BioAgeAccel as a mediator for associations between heart irradiation (heart-RT) and anthracyclines with CVDs. Both individual biomarkers and principal components–based composite indices were examined with Bonferroni correction. Results: Among 2,941 survivors (52.9% male; median age 33.5 years), most BioAgeAccel measures were elevated after high-dose heart-RT, with fewer observed for high-dose anthracyclines. PCGrimAge, which predicts lifespan and health span, was most strongly associated with MI odds ratio (OR) = 1.85; 95% confidence interval (CI), 1.45–2.36, whereas DNAmCRP was most strongly associated with cardiomyopathy (OR = 1.31; 95% CI, 1.14–1.50). Mediation analyses showed BioAgeAccel accounted for substantial proportions of treatment–CVD associations, particularly for heart-RT with MI (up to 25.7%) and cardiomyopathy (up to 30.3%) and anthracyclines with cardiomyopathy (7.5%). Integrating multiple biomarkers via principal component analysis yielded greater mediation than the best individual measure (31.6%, 35.9%, and 7.7% for the three pairs, respectively). Conclusions: BioAgeAccel measures vary in their associations with CVDs and in their mediation of treatment-related cardiotoxicity. Impact: These findings highlight the potential of DNAm-based aging biomarkers to identify high-risk survivors, enhance risk stratification, and guide targeted interventions to reduce the long-term CVD burden.