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Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
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.
Afiliação
  • Garcia-Pavia P; Hospital Universitario Puerta de Hierro, Madrid, Spain (P.G.-P., M.A.R.-C., F.D., L.A.-P.).
  • Kim Y; Centro de Investigación Biomédica en Red Enfermedades in Cardiovascular Diseases (CIBERCV), Madrid, Spain (P.G.-P., M.A.R.-C., A.B.-G., J. Lupon, D.A.P.-F., J.M.G.-P., F.D., E.L.-P., L.A.-P.).
  • Restrepo-Cordoba MA; University Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain (P.G.-P.).
  • Lunde IG; Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
  • Wakimoto H; Massachusetts General Hospital, Boston (Y.K.).
  • Smith AM; Hospital Universitario Puerta de Hierro, Madrid, Spain (P.G.-P., M.A.R.-C., F.D., L.A.-P.).
  • Toepfer CN; Centro de Investigación Biomédica en Red Enfermedades in Cardiovascular Diseases (CIBERCV), Madrid, Spain (P.G.-P., M.A.R.-C., A.B.-G., J. Lupon, D.A.P.-F., J.M.G.-P., F.D., E.L.-P., L.A.-P.).
  • Getz K; Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
  • Gorham J; Oslo University Hospital and University of Oslo, Norway (I.G.L.).
  • Patel P; Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
  • Ito K; Perelman School of Medicine and University of Pennsylvania Health System, Philadelphia (A.M.S., K.G., Z.A., J. Li, A.T.O., B.F., R.A., B.K.).
  • Willcox JA; Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
  • Arany Z; University of Oxford (C.N.T.).
  • Li J; Perelman School of Medicine and University of Pennsylvania Health System, Philadelphia (A.M.S., K.G., Z.A., J. Li, A.T.O., B.F., R.A., B.K.).
  • Owens AT; Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
  • Govind R; Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
  • Nuñez B; Brigham and Women's Hospital, Boston MA (P.P., C.E.S.).
  • Mazaika E; Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
  • Bayes-Genis A; Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
  • Walsh R; Perelman School of Medicine and University of Pennsylvania Health System, Philadelphia (A.M.S., K.G., Z.A., J. Li, A.T.O., B.F., R.A., B.K.).
  • Finkelman B; Perelman School of Medicine and University of Pennsylvania Health System, Philadelphia (A.M.S., K.G., Z.A., J. Li, A.T.O., B.F., R.A., B.K.).
  • Lupon J; Perelman School of Medicine and University of Pennsylvania Health System, Philadelphia (A.M.S., K.G., Z.A., J. Li, A.T.O., B.F., R.A., B.K.).
  • Whiffin N; National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
  • Serrano I; Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
  • Midwinter W; Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Spain (B.N., M.P.).
  • Wilk A; National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
  • Bardaji A; Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
  • Ingold N; Centro de Investigación Biomédica en Red Enfermedades in Cardiovascular Diseases (CIBERCV), Madrid, Spain (P.G.-P., M.A.R.-C., A.B.-G., J. Lupon, D.A.P.-F., J.M.G.-P., F.D., E.L.-P., L.A.-P.).
  • Buchan R; Hospital Universitario Germans Trias i Pujol, Badalona, Spain (A.B.-G., J. Lupon).
  • Tayal U; National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
  • Pascual-Figal DA; Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
  • de Marvao A; Perelman School of Medicine and University of Pennsylvania Health System, Philadelphia (A.M.S., K.G., Z.A., J. Li, A.T.O., B.F., R.A., B.K.).
  • Ahmad M; Centro de Investigación Biomédica en Red Enfermedades in Cardiovascular Diseases (CIBERCV), Madrid, Spain (P.G.-P., M.A.R.-C., A.B.-G., J. Lupon, D.A.P.-F., J.M.G.-P., F.D., E.L.-P., L.A.-P.).
  • Garcia-Pinilla JM; Hospital Universitario Germans Trias i Pujol, Badalona, Spain (A.B.-G., J. Lupon).
  • Pantazis A; National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
  • Dominguez F; Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
  • John Baksi A; MRC London Institute of Medical Sciences, Imperial College UK (N.W., D.P.O., S.A.C., J.S.W., C.E.S., A.d.M.).
  • O'Regan DP; Hospital Universitario de Tarragona Joan XXIII. IISPV, Rovira Virgili University, Spain (I.S., A.B.).
  • Rosen SD; National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
  • Prasad SK; Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
  • Lara-Pezzi E; National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
  • Provencio M; Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
  • Lyon AR; Hospital Universitario de Tarragona Joan XXIII. IISPV, Rovira Virgili University, Spain (I.S., A.B.).
  • Alonso-Pulpon L; National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
  • Cook SA; Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
  • DePalma SR; National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
  • Barton PJR; Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
  • Aplenc R; National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
  • Seidman JG; Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
  • Ky B; Centro de Investigación Biomédica en Red Enfermedades in Cardiovascular Diseases (CIBERCV), Madrid, Spain (P.G.-P., M.A.R.-C., A.B.-G., J. Lupon, D.A.P.-F., J.M.G.-P., F.D., E.L.-P., L.A.-P.).
Circulation ; 140(1): 31-41, 2019 07 02.
Article em En | MEDLINE | ID: mdl-30987448
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. CLINICAL TRIAL REGISTRATION URL https//www.clinicaltrials.gov . Unique identifiers NCT01173341; AAML1031; NCT01371981.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Variação Genética / Cardiomiopatias / Neoplasias / Antineoplásicos Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies Limite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Circulation Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Variação Genética / Cardiomiopatias / Neoplasias / Antineoplásicos Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies Limite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Circulation Ano de publicação: 2019 Tipo de documento: Article