دورية أكاديمية
أعرض في EDS

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

التفاصيل البيبلوغرافية
العنوان: Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy
المؤلفون: Garcia-Pavia, Pablo, Kim, Yuri, Restrepo-Cordoba, Maria Alejandra, Lunde, Ida G, Wakimoto, Hiroko, Smith, Amanda M, Toepfer, Christopher N, Getz, Kelly, Gorham, Joshua, Patel, Parth, Ito, Kaoru, Willcox, Jonathan A, Arany, Zoltan, Li, Jian, Owens, Anjali T, 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, de Marvao, Antonio, Ahmad, Mian, Garcia-Pinilla, Jose Manuel, Pantazis, Antonis, Dominguez, Fernando, John Baksi, A, O'Regan, Declan P, Rosen, Stuart D, Prasad, Sanjay K, Lara-Pezzi, Enrique, Provencio, Mariano, Lyon, Alexander R, Alonso-Pulpon, Luis, Cook, Stuart A, DePalma, Steven R, Barton, Paul J R, Aplenc, Richard, Seidman, Jonathan G, Ky, Bonnie, Ware, James S, Seidman, Christine E
المساهمون: 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)
بيانات النشر: American Heart Association (AHA)
سنة النشر: 2019
المجموعة: REPISALUD (REPositorio Institucional en SALUD del Instituto de Salud Carlos III - ISCIII)
مصطلحات موضوعية: Cardiomyopathies, Drug therapy, Genetics, Medical oncology, Titin
الوصف: 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<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and ...
نوع الوثيقة: article in journal/newspaper
اللغة: English
تدمد: 0009-7322
1524-4539
العلاقة: https://doi.org/10.1161/CIRCULATIONAHA.118.037934Test; info:eu-repo/grantAgreement/ES/SEV-2015-0505; info:eu-repo/grantAgreement/ES/PI15/01551; info:eu-repo/grantAgreement/ES/PI17/01941; info:eu-repo/grantAgreement/ES/CB16/11/00432; info:eu-repo/grantAgreement/ES/SAF2015-71863-REDT; Circulation. 2019; 140(1):31-41; http://hdl.handle.net/10668/13834Test; http://hdl.handle.net/20.500.12105/7992Test; Circulation
DOI: 10.1161/CIRCULATIONAHA.118.037934
الإتاحة: https://doi.org/20.500.12105/7992Test
https://doi.org/10.1161/CIRCULATIONAHA.118.037934Test
http://hdl.handle.net/10668/13834Test
https://hdl.handle.net/20.500.12105/7992Test
حقوق: http://creativecommons.org/licenses/by/4.0Test/ ; Atribución 4.0 Internacional ; open access
رقم الانضمام: edsbas.3D8434E7
قاعدة البيانات: BASE
الوصف
تدمد:00097322
15244539
DOI:10.1161/CIRCULATIONAHA.118.037934