In a groundbreaking study published in JAMA Network Open on June 20, 2025, researchers from St. Jude Children’s Research Hospital have unveiled new insights into the genetic underpinnings of late-onset cardiomyopathy among long-term survivors of childhood cancer. Cardiomyopathy, a debilitating and often fatal disease characterized by the weakening of the heart muscle and subsequent heart failure, poses a significantly increased risk for childhood cancer survivors, yet the genetic mechanisms influencing this risk have remained elusive. This pioneering research elucidates how common genetic variants in the genes TTN and BAG3 are associated with a decreased risk of late-onset cardiomyopathy in this vulnerable population, while rare variants linked to early-onset cardiomyopathy in other groups do not have the same impact.
Childhood cancer survivors experience cardiomyopathy at rates up to fifteen times higher than their healthy siblings, a disparity primarily attributed to the cardiotoxic side effects of cancer therapies such as anthracycline chemotherapy and radiation. The complex interplay between treatment exposures, age at diagnosis, and traditional cardiovascular risk factors only partially explains this elevated prevalence. Genetic predisposition has long been suspected as a critical factor, but the specifics remained undefined until now. The meticulous work carried out by Dr. Yadav Sapkota and colleagues at St. Jude brings clarity to these genetic factors by focusing on TTN and BAG3—genes that play critical roles in cardiac muscle structure and regulation.
TTN encodes titin, the largest known human protein, fundamental to the structural integrity and elasticity of cardiac sarcomeres. Mutations in TTN have been implicated in various cardiomyopathies due to impaired mechanical stability and signaling within cardiac muscle cells. BAG3, on the other hand, encodes a multifunctional co-chaperone protein involved in protein quality control and autophagy, processes vital for the maintenance of cardiac myocyte health. Disruptions in BAG3 function have been connected to myofibrillar myopathy and dilated cardiomyopathy. Understanding how variations in these genes influence cardiomyopathy risk after cancer therapy could revolutionize risk stratification and patient management.
The team performed their analysis using a cohort drawn from two extensive survivor groups: the St. Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS). They analyzed genetic variants found in survivors who developed late-onset cardiomyopathy at least five years post-cancer treatment, contrasting their findings with known data from the general population’s dilated cardiomyopathy cases and adult cancer survivor datasets. This comparative approach allowed them to discern how genetic risks diverge between childhood and adult cancer survivor populations as well as from familial forms of cardiomyopathy.
One of the most striking revelations concerns the dichotomy between early- and late-onset cardiomyopathy genetically. Familial, early-onset cardiomyopathy is often driven by rare pathogenic variants with strong effect sizes found in families with a history of the disease. These variants typically manifest in youth or early adulthood. In contrast, late-onset cardiomyopathy in the general population tends to be sporadic and influenced by common variants that exert more modest, cumulative effects. The study showed common variants in TTN and BAG3 conferred a protective effect against late-onset cardiomyopathy in childhood cancer survivors similar to patterns observed in the general population.
Conversely, rare variants previously associated with a heightened risk of early-onset cardiomyopathy neither predicted nor correlated with late-onset cardiomyopathy in survivors of childhood cancer. This finding challenges the pre-existing assumption that the genetic architecture of cancer therapy-related cardiomyopathy mirrors that of familial dilated cardiomyopathy or that observed in adult cancer survivors. Instead, it highlights that the genetic determinants of cardiotoxicity in pediatric cancer survivors form a distinct spectrum, shaped by unique biological interactions between treatment injury and genetic background.
Dr. Sapkota emphasized these findings in the context of familial versus sporadic disease mechanisms: "Rare variants typically perturb cardiomyocyte function early in life, leading to aggressive disease onset. Our data indicate these rare variants do not contribute substantially to the late-onset cardiomyopathy observed after childhood cancer, underscoring a different genetic etiology for these survivors." He added that common variants appear to modulate risk more subtly but meaningfully over decades, paralleling the sporadic dilated cardiomyopathy trends noted in the broader population.
These nuanced genetic discoveries open the door to more tailored screening strategies for childhood cancer survivors, integrating polygenic risk profiling to complement traditional clinical factors such as cancer treatment history and cardiac imaging surveillance. By refining individual risk prediction models, clinicians could identify individuals at greatest risk for late cardiomyopathy, enabling earlier intervention and potentially modifying lifestyle or treatment plans to mitigate cardiac deterioration.
Furthermore, the research underscores the complexity of childhood cancer survivorship as a distinct clinical domain requiring dedicated genomics-driven investigation. It draws attention to the necessity for longitudinal studies that combine large-scale genetic data with deep phenotyping and treatment exposure records. Future studies expanding upon these findings could explore gene-environment interactions, epigenetic modifications, and potential therapeutic targets to preserve cardiac function in this growing population.
Funded by multiple grants from the National Institutes of Health and supported by the American Lebanese Syrian Associated Charities (ALSAC), the study represents a collaborative effort among experts from institutions including the University of Minnesota, Baylor College of Medicine, Fred Hutchinson Cancer Center, University of Alabama at Birmingham, Northwestern University, and others, reflecting a multidisciplinary approach imperative for unraveling such complex disease processes.
As survival rates continue to improve for children diagnosed with cancer—with overall survival now surpassing 80% due to advances pioneered at institutions like St. Jude—the imperative to understand and prevent long-term adverse outcomes like cardiomyopathy grows ever more urgent. This research marks a pivotal step toward that goal, illuminating distinct genetic pathways that could inform precision medicine approaches aiming to improve quality of life and cardiovascular health in childhood cancer survivors worldwide.
In summary, this landmark study delineates a clear genetic divergence between early- and late-onset cardiomyopathy forms in childhood cancer survivors, identifying common variant protective effects within TTN and BAG3 and nullifying the presumed role of rare variants in late-onset cases. These insights change the landscape of cardiotoxicity research and bear profound implications for clinical practice, genetic counseling, and future therapeutic development.
Subject of Research: Genetic risk factors for late-onset cancer therapy-related cardiomyopathy in long-term survivors of childhood cancer
Article Title: TTN and BAG3 in Cancer Therapy–Related Cardiomyopathy Among Long-Term Survivors of Childhood Cancer
News Publication Date: June 20, 2025
Web References:
- St. Jude Lifetime Cohort (SJLIFE)
- Childhood Cancer Survivor Study (CCSS)
- Yadav Sapkota profile at St. Jude
- Epidemiology & Cancer Control Department at St. Jude
- DOI link to article
Image Credits: St. Jude Children’s Research Hospital
Keywords: Cardiomyopathy, childhood cancer survivorship, TTN, BAG3, genetic variants, late-onset cardiomyopathy, cancer therapy cardiotoxicity, dilated cardiomyopathy, cancer survivor genetics
