Autor según el artículo: Garcia-Pavia, Pablo; Kim, Yuri; Alejandra Restrepo-Cordoba, Maria; 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; Nunez, 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; Manuel Garcia-Pinilla, Jose; Pantazis, Antonis; Dominguez, Fernando; Baksi, A John; 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
Departamento: Medicina i Cirurgia
Autor/es de la URV: Bardají Ruiz, Alfredo
Palabras clave: Titin Polymorphisms Mutations Medical oncology Genetics Familial dilated cardiomyopathy Echocardiography Drug therapy Congestive-heart-failure Chemotherapy Cardiotoxicity Cardiomyopathies American society A-band truncation medical oncology genetics drug therapy cardiomyopathies
Resumen: 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.
Áreas temáticas: Saúde coletiva Physiology (medical) Peripheral vascular disease Nutrição Medicina iii Medicina ii Medicina i Interdisciplinar Hematology General medicine Farmacia Ensino Engenharias iv Engenharias ii Enfermagem Educação física Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciência da computação Cardiology and cardiovascular medicine Cardiac & cardiovascular systems Biotecnología
Acceso a la licencia de uso: https://creativecommons.org/licenses/by/3.0/es/
ISSN: 00097322
Direcció de correo del autor: alfredo.bardaji@urv.cat
Identificador del autor: 0000-0003-1900-6974
Fecha de alta del registro: 2024-11-09
Versión del articulo depositado: info:eu-repo/semantics/publishedVersion
Enlace a la fuente original: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.037934
URL Documento de licencia: https://repositori.urv.cat/ca/proteccio-de-dades/
Referencia al articulo segun fuente origial: Circulation. 140 (1): 31-41
Referencia de l'ítem segons les normes APA: Garcia-Pavia, Pablo; Kim, Yuri; Alejandra Restrepo-Cordoba, Maria; Lunde, Ida G; Wakimoto, Hiroko; Smith, Amanda M; Toepfer, Christopher N; Getz, Kell (2019). Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy. Circulation, 140(1), 31-41. DOI: 10.1161/CIRCULATIONAHA.118.037934
DOI del artículo: 10.1161/CIRCULATIONAHA.118.037934
Entidad: Universitat Rovira i Virgili
Año de publicación de la revista: 2019
Tipo de publicación: Journal Publications
Repositori URV