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Repisalud author Garcia-Pavia, Pablo author Kim, Yuri author Restrepo-Cordoba, Maria Alejandra author Lunde, Ida G author Wakimoto, Hiroko author Smith, Amanda M author Toepfer, Christopher N author Getz, Kelly author Gorham, Joshua author Patel, Parth author Ito, Kaoru author Willcox, Jonathan A author Arany, Zoltan author Li, Jian author Owens, Anjali T author Govind, Risha author Nuñez, Beatriz author Mazaika, Erica author Bayes-Genis, Antoni author Walsh, Roddy author Finkelman, Brian author Lupon, Josep author Whiffin, Nicola author Serrano, Isabel author Midwinter, William author Wilk, Alicja author Bardaji, Alfredo author Ingold, Nathan author Buchan, Rachel author Tayal, Upasana author Pascual-Figal, Domingo A author de Marvao, Antonio author Ahmad, Mian author Garcia-Pinilla, Jose Manuel author Pantazis, Antonis author Dominguez, Fernando author John Baksi, A author O'Regan, Declan P author Rosen, Stuart D author Prasad, Sanjay K author Lara-Pezzi, Enrique author Provencio, Mariano author Lyon, Alexander R author Alonso-Pulpon, Luis author Cook, Stuart A author DePalma, Steven R author Barton, Paul J R author Aplenc, Richard author Seidman, Jonathan G author Ky, Bonnie author Ware, James S author Seidman, Christine E funder Instituto de Salud Carlos III funder Ministerio de Economía y Competitividad (España) funder Wellcome Trust funder Medical Research Council (Reino Unido) funder National Institute for Health Research (Reino Unido) funder Imperial College London (Reino Unido) funder Fondation Leducq funder British Heart Foundation funder National Institutes of Health (Estados Unidos) funder Howard Hughes Medical Institute funder Fundación ProCNIC funder Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 2019-07-30T08:44:30Z 2019-07-30T08:44:30Z 2019-07-02 Circulation. 2019; 140(1):31-41 0009-7322 http://hdl.handle.net/10668/13834 http://hdl.handle.net/20.500.12105/7992 30987448 10.1161/CIRCULATIONAHA.118.037934 1524-4539 Circulation 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 adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981. eng Cardiomyopathies Drug therapy Genetics Medical oncology Titin Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy journal article 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 URL https://repisalud.isciii.es/bitstreams/371bb359-0253-4380-9c73-804f4f0c68d0/download File MD5 48671363bae6dbda6b4dbdb38d65b43b 313178 application/pdf GeneticVariantsAssociatedWith_2019.pdf URL https://repisalud.isciii.es/bitstreams/9d06bd96-6aae-41de-be3f-c1031cbb9999/download File MD5 372a222a297dab74a938d2fba6541a3a 332173 application/pdf GeneticVariantsAssociatedWith_2019_supplmat.pdf URL https://repisalud.isciii.es/bitstreams/031b312e-634c-49e4-96d7-eafe554e616d/download File MD5 571769096eb39a4a2cf887fd9b5895f4 65250 text/plain GeneticVariantsAssociatedWith_2019.pdf.txt URL https://repisalud.isciii.es/bitstreams/8b08adb7-6b04-4726-b920-6f39e18d3f59/download File MD5 8a69c3d6769163cd0f3c1437a4163f46 34623 text/plain GeneticVariantsAssociatedWith_2019_supplmat.pdf.txt