Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy. Lara-Pezzi, Enrique Provencio, Mariano Lyon, Alexander R. De Marvao, Antonio Ahmad, Mian Garcia-Pinilla, Jose Manuel Pantazis, Antonis Dominguez, Fernando John Baksi, A. Govind, Risha Nuñez, Beatriz Mazaika, Erica Bayes-Genis, Antoni Walsh, Roddy Finkelman, Brian Lupon, Josep Whiffin, Nicola Serrano, Isabel Midwinter, William Wilk, Alicja Bardaji, Alfredo Ingold, Nathan Buchan, Rachel Tayal, Upasana Pascual-Figal, Domingo A. Getz, Kelly Gorham, Joshua Patel, Parth Ito, Kaoru Willcox, Jonathan A. Garcia-Pavia, Pablo Kim, Yuri Restrepo-Cordoba, Maria Alejandra Lunde, Ida G. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. Conclusions: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type (P=0.0004 and P<0.002, respectively). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation (P=0.003) and impaired myocardial recovery (P=0.03) than those without. Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants (P=7.36e-08), 0.7% of healthy volunteers (P=3.42e-06), and 0.6% of the reference population (P=5.87e-14). Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts (P≤1.98e-04). Adult patients with CCM had cardiovascular risk factors similar to the US population. Results: CCM was diagnosed 0.4 to 9 years after chemotherapy 90% of these patients received anthracyclines. A prevalent CCM genotype was modeled in anthracycline-treated mice. Clinical characteristics and outcomes were assessed and stratified by genotypes. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Cardiomyopathy genes, including 9 prespecified genes, were sequenced. Methods: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). We hypothesized that rare variants in cardiomyopathy genes contribute to CCM.
These parameters incompletely account for substantial interindividual susceptibility to CCM. Background: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders.
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