Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy
| Autor: | Garcia-Pavia, P, Kim, Y, Restrepo-Cordoba, MA, Lunde, IG, Wakimoto, H, Smith, AM, Toepfer, CN, Getz, K, Gorham, J, Patel, P, Ito, K, Willcox, JA, Arany, Z, Li, J, Owens, AT, Govind, R, Nuñez, B, Mazaika, E, Bayes-Genis, A, Walsh, R, Finkelman, B, Lupon, J, Whiffin, N, Serrano, I, Midwinter, W, Wilk, A, Bardaji, A, Ingold, N, Buchan, R, Tayal, U, Pascual-Figal, DA, De Marvao, A, Ahmad, M, Garcia-Pinilla, JM, Pantazis, A, Dominguez, F, John Baksi, A, O'Regan, DP, Rosen, SD, Prasad, SK, Lara-Pezzi, E, Provencio, M, Lyon, AR, Alonso-Pulpon, L, Cook, SA, DePalma, SR, Barton, PJR, Aplenc, R, Seidman, JG, Ky, B, Ware, JS, Seidman, CE |
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| Přispěvatelé: | Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Wellcome Trust, Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Imperial College London (Reino Unido), Fondation Leducq, British Heart Foundation, National Institutes of Health (Estados Unidos), Howard Hughes Medical Institute, Fundación ProCNIC, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Department of Health, Royal Brompton & Harefield NHS Foundation Trust, Imperial College Healthcare NHS Trust- BRC Funding, Rosetrees Trust, The Academy of Medical Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
CARDIOTOXICITY
cardiomyopathies Adult Male Cardiac & Cardiovascular Systems FAMILIAL DILATED CARDIOMYOPATHY Antineoplastic Agents Mice Transgenic TITIN 1117 Public Health and Health Services Cohort Studies Mice Neoplasms A-BAND TRUNCATION Animals Humans genetics titin Prospective Studies AMERICAN SOCIETY 1102 Cardiorespiratory Medicine and Haematology POLYMORPHISMS Aged Retrospective Studies Science & Technology CONGESTIVE-HEART-FAILURE MUTATIONS Genetic Variation 1103 Clinical Sciences CHEMOTHERAPY Middle Aged medical oncology drug therapy Mice Inbred C57BL Peripheral Vascular Disease Cardiovascular System & Hematology Cardiovascular System & Cardiology Female ECHOCARDIOGRAPHY Cardiomyopathies Life Sciences & Biomedicine |
| Zdroj: | Circulation r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol instname Repisalud Instituto de Salud Carlos III (ISCIII) |
| ISSN: | 0009-7322 |
| Popis: | BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. 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). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. 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. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). 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). 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. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P |
| Databáze: | OpenAIRE |
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