TTN and BAG3 in Cancer Therapy-Related Cardiomyopathy among Long-Term Survivors of Childhood Cancer

Importance: Cancer therapy-related cardiomyopathy (CCM) is an important concern for childhood cancer survivors. In the general population, rare variants in TTN and BAG3 are associated with an increased risk of familial dilated cardiomyopathy, and common variants are associated with a decreased risk of sporadic dilated cardiomyopathy. Objectives: To examine associations of common and rare protein-altering variants (PAVs) in TTN and BAG3 with late-onset CCM risk in childhood cancer survivors. Design, Setting, and Participants: This retrospective cohort study with a prospective follow-up included childhood cancer survivors from the St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS) with prior exposure to anthracyclines and/or chest-directed radiation. Cancer therapy-related cardiomyopathy was clinically assessed in SJLIFE and self-reported in CCSS, with severity graded using Common Terminology Criteria for Adverse Events, version 4.03. The data analysis was conducted from January 4, 2023, to March 6, 2025. Exposure: Late-onset CCM. Main Outcome and Measures: Multivariable logistic regression was used to evaluate the association of common variants in TTN and BAG3 with late-onset CCM risk, adjusting for relevant demographic and cancer treatment exposures. In SJLIFE alone, 7 echocardiographic parameters were assessed. Rare PAVs were examined using Fisher exact test. Cohort-specific results were combined using meta-analytic approaches. Results: The cohort included 1843 childhood cancer survivors from SJLIFE (median [IQR] age at CCM diagnosis, 34.9 [28.0-42.3] years; 53.2% male) and 4577 from CCSS (median [IQR] age at CCM diagnosis, 32.0 [23.0-41.0] years; 51.6% female). In the combined sample of European ancestry survivors from SJLIFE (205 with CCM grade ≥2) and CCSS (248 with CCM grade ≥2), common variants rs3829746-C in TTN (odds ratio, 0.81; 95% CI, 0.68-0.97) and rs2234962-C in BAG3 (odds ratio, 0.79; 95% CI, 0.65-0.95) were associated with a decreased risk of late-onset CCM. In SJLIFE African ancestry survivors, no association was observed with either of the common variants. Rare PAVs were not associated with late-onset CCM in European or African ancestry survivors. In European ancestry survivors, both rs3829746-C and rs2234962-C were also associated with reduced left ventricular end-systolic volume (β [SE], -1.90 [0.65] and -2.68 [0.64], respectively) and global longitudinal peak strain (β [SE], -0.31 [0.13] and -0.30 [0.12]) and with increased left ventricular ejection fraction (β [SE], 0.62 [0.27] and 0.86 [0.27], respectively). Conclusions and Relevance: The findings of this cohort study show that common variants in TTN and BAG3 are associated with a decreased risk of late-onset CCM among childhood cancer survivors, while rare PAVs showed no association.