What does this research mean for the field?

A composite measure of biological age acceleration mediates 35.9% of the association between heart radiation and cardiomyopathy, and 31.6% of the association with myocardial infarction in childhood cancer survivors. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To assess how various measures of biological age acceleration relate to cardiotoxicity and cardiovascular risk in childhood cancer survivors.

April 5, 2026

Abstract 867: Cancer treatment-related cardiotoxicity among survivors of childhood cancer: A comparative and integrated view of multiple measures of biological age acceleration.

Key Result

A composite measure of biological age acceleration mediated 35.9% of the heart radiation-cardiomyopathy association and 31.6% of the radiation-myocardial infarction link in cancer survivors.

Key Points

To assess how various measures of biological age acceleration relate to cardiotoxicity and cardiovascular risk in childhood cancer survivors.
Analyzed DNA methylation profiles from 2,941 participants in the St. Jude Lifetime Cohort.
Defined cardiovascular disease as either cardiomyopathy or myocardial infarction.
Used multiple DNA methylation biomarkers including epigenetic clocks and other molecular markers.
Evaluated associations between treatment exposures and cardiovascular outcomes using logistic regression models.
9.4% of survivors developed cardiomyopathy, and 2.3% developed myocardial infarction.
GrimAge showed the strongest association with myocardial infarction (OR=1.85).
DNAmCRP had the strongest association with cardiomyopathy (OR=1.31).
Composite BioAgeAccel measure accounted for significant portions of the associations between treatment exposures and cardiovascular events.

Structured PICO

Does biological age acceleration mediate the relationship between cardiotoxic cancer treatments and cardiovascular disease in childhood cancer survivors?

Population

2,941 childhood cancer survivors from the St. Jude Lifetime Cohort, median age at cancer diagnosis 6.1 years, median age at DNAm blood draw 30.1 years.

Intervention

Cardiotoxic treatment exposures (radiation potentially exposing the heart [heart-RT] and anthracycline chemotherapy) and biological age acceleration (BioAgeAccel) assessed via 43 DNAm-based biomarkers.

Outcome

Cardiovascular disease (CVD) defined as either cardiomyopathy or myocardial infarction (MI).hard clinical

DNA methylation-based biological age acceleration biomarkers are associated with and partially mediate the risk of long-term cardiovascular disease in childhood cancer survivors exposed to cardiotoxic therapies.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Abstract Introduction: Mounting evidence suggests that childhood cancer survivors experience biological age acceleration (BioAgeAccel) and are at increased risk for cardiovascular disease. We performed an integrated analysis of multiple BioAgeAccel measures to examine how aging relates to treatment-related toxicity and cardiovascular risk, and how biomarkers developed under different methodological schemes capture this pathway. Methods: Cardiovascular disease (CVD) was defined as either cardiomyopathy or myocardial infarction (MI). DNA methylation (DNAm) profiles of peripheral-blood-mononuclear-cells from 2,941 St. Jude Lifetime Cohort participants were generated using Illumina EPIC BeadChips. Biological age was assessed using 43 DNAm-based biomarkers, including epigenetic clocks such as GrimAge, PhenoAge, and DunedinPACE, as well as molecular biomarkers such as C-reactive protein (DNAmCRP). BioAgeAccel was defined as residuals from regressing biological age on chronological age at DNAm blood draw (except DunedinPACE). Cardiotoxic treatment exposures included radiation potentially exposing the heart (heart-RT; mean dose 15 Gy considered high-dose) and anthracycline chemotherapy (cumulative dose ≥250 mg/m2 doxorubicin equivalents considered high-dose). Multivariable logistic regression models evaluated the associations of each biomarker with CVD. BioAgeAccel was also evaluated as a mediator between heart-RT or anthracycline exposure and CVD to examine its role in the causal pathway. Mediation analyses were conducted for each biomarker individually and for a composite measure derived from principal component analysis. Results: Median age at cancer diagnosis was 6.1 years (range 0-23.6; Q1-Q3: 2.8-12.6), and at DNAm blood draw was 30.1 years (range 0.2-66.6; Q1-Q3: 21.7-38.0). Overall, 9.4% developed cardiomyopathy (median onset 34.7 years), and 2.3% developed MI (median onset 40.7 years). Most BioAgeAccel measures were elevated after high-dose heart-RT, with fewer associations for high-dose anthracyclines. PC version of GrimAge showed the strongest association with MI (OR=1.85, 95%CI: 1.45-2.36; Bonferroni P=4.06E-05), and DNAmCRP showed the strongest association with cardiomyopathy (OR=1.31, 95%CI: 1.14-1.50; Bonferroni P=5.17E-03). Mediation estimates varied across biomarkers. A composite BioAgeAccel measure accounted for 31.6% of the heart-RT-MI association, 35.9% of the heart-RT-cardiomyopathy association, and 7.7% of the anthracycline-cardiomyopathy association. Conclusions: BioAgeAccel measures vary in their associations with cardiotoxicities and treatment-related aging pathways. These findings support further refinement and validation of DNAm-based aging biomarkers to advance future risk stratification and targeted prevention of long-term CVD in survivors. Citation Format: Xiaoxi Meng, Tiffany Eulalio, Kwangyeon Oh, Noel-Marie Plonski, Kyla Shelton, Heather L. Mulder, John B. Easton, Jinghui Zhang, Emily Walker, Geoffrey A. Neale, Deo Kumar Srivastava, Rebecca M. Howell, Jeanne S. Mandelblatt, Bonnie Ky, Stephanie B. Dixon, Gregory T. Armstrong, Melissa Maria Hudson, Kirsten K. Ness, Zhaoming Wang. Cancer treatment-related cardiotoxicity among survivors of childhood cancer: A comparative and integrated view of multiple measures of biological age acceleration abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 867.

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