Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy
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View abstract on PubMed
Summary
This summary is machine-generated.Rare genetic variants, especially in the Titin gene, significantly increase the risk of cancer therapy-induced cardiomyopathy (CCM). Identifying these variants aids in predicting and managing CCM risk in cancer patients.
Area Of Science
- Cardiology
- Genetics
- Oncology
Background
- Cancer therapy-induced cardiomyopathy (CCM) risk is incompletely explained by cumulative drug exposure and pre-existing conditions.
- Substantial inter-individual susceptibility to CCM suggests underlying genetic factors.
- Hypothesis: Rare variants in cardiomyopathy genes contribute to CCM development.
Purpose Of The Study
- To investigate the role of rare variants in cardiomyopathy genes in the development of CCM.
- To compare the prevalence of these variants in CCM patients versus control populations.
- To assess the clinical impact of specific genetic variants on CCM outcomes.
Main Methods
- Sequenced cardiomyopathy genes in 213 CCM patients across three cohorts (adults with diverse cancers, adults with breast cancer, children with acute myeloid leukemia).
- Compared rare variant prevalence against The Cancer Genome Atlas (TCGA), healthy volunteers, and a reference population.
- Assessed clinical characteristics, outcomes, and modeled a prevalent genotype in mice.
Main Results
- CCM patients exhibited a higher prevalence of rare protein-altering variants in 9 prioritized cardiomyopathy genes compared to controls.
- Titin-truncating variants (TTNtvs) were significantly more common in CCM patients (7.5%) than in TCGA (1.1%), healthy volunteers (0.7%), and the reference population (0.6%).
- Adults with CCM and TTNtvs experienced increased heart failure, atrial fibrillation, and impaired myocardial recovery.
Conclusions
- Unrecognized rare variants, particularly TTNtvs, elevate CCM risk in both pediatric and adult cancer patients.
- Genetic profiling, combined with chemotherapy dosage and traditional risk factors, enhances CCM risk stratification.
- TTNtv mouse models and cardiomyocytes confirm sustained contractile dysfunction upon anthracycline exposure.
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