Articles producció científica> Medicina i Cirurgia

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

  • Identification data

    Identifier: imarina:5761447
    Authors:
    Garcia-Pavia, PabloKim, YuriAlejandra Restrepo-Cordoba, MariaLunde, Ida G.Wakimoto, HirokoSmith, Amanda M.Toepfer, Christopher N.Getz, KellyGorham, JoshuaPatel, ParthIto, KaoruWillcox, Jonathan A.Arany, ZoltanLi, JianOwens, Anjali T.Govind, RishaNunez, BeatrizMazaika, EricaBayes-Genis, AntoniWalsh, RoddyFinkelman, BrianLupon, JosepWhiffin, NicolaSerrano, IsabelMidwinter, WilliamWilk, AlicjaBardaji, AlfredoIngold, NathanBuchan, RachelTayal, UpasanaPascual-Figal, Domingo A.de Marvao, AntonioAhmad, MianManuel Garcia-Pinilla, JosePantazis, AntonisDominguez, FernandoBaksi, A. JohnO'Regan, Declan P.Rosen, Stuart D.Prasad, Sanjay K.Lara-Pezzi, EnriqueProvencio, MarianoLyon, Alexander R.Alonso-Pulpon, LuisCook, Stuart A.DePalma, Steven R.Barton, Paul J. R.Aplenc, RichardSeidman, Jonathan G.Ky, BonnieWare, James S.Seidman, Christine E.
    Abstract:
    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 cardiomyoc
  • Others:

    Author, as appears in the article.: 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.;
    Department: Medicina i Cirurgia
    URV's Author/s: Bardají Ruiz, Alfredo
    Keywords: 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
    Abstract: 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.
    Thematic Areas: 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
    licence for use: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 00097322
    Author's mail: alfredo.bardaji@urv.cat
    Author identifier: 0000-0003-1900-6974
    Record's date: 2023-02-22
    Papper version: info:eu-repo/semantics/publishedVersion
    Link to the original source: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.037934
    Papper original source: Circulation. 140 (1): 31-41
    APA: Garcia-Pavia, Pablo; Kim, Yuri; Alejandra Restrepo-Cordoba, Maria; Lunde, Ida G.; Wakimoto, Hiroko; Smith, Amanda M.; Toepfer, Christopher N.; Getz, K (2019). Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy. Circulation, 140(1), 31-41. DOI: 10.1161/CIRCULATIONAHA.118.037934
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Article's DOI: 10.1161/CIRCULATIONAHA.118.037934
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2019
    Publication Type: Journal Publications
  • Keywords:

    Cardiac & Cardiovascular Systems,Cardiology and Cardiovascular Medicine,Hematology,Peripheral Vascular Disease,Physiology (Medical)
    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
    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
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