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Cited by 357

The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.

Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy

Open access
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.·2019·Circulation
DOI 10.1161/circulationaha.118.037934
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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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Authors
Garcia-Pavia, P., Kim, Y., Restrepo-Cordoba, M. A., Lunde, I. G., Wakimoto, H., Smith, A. M., Toepfer, C. N., Getz, K., Gorham, J., Patel, P., Ito, K., Willcox, J. A., Arany, Z., Li, J., Owens, A. T., Govind, R., Nuñez, B., Mazaika, E., Bayes-Genis, A., Walsh, R., Finkelman, B., Lupon, J., Whiffin, N., Serrano, I., Midwinter, W., Wilk, A., Bardaji, A., Ingold, N., Buchan, R., Tayal, U., Pascual-Figal, D. A., de Marvao, A., Ahmad, M., Garcia-Pinilla, J. M., Pantazis, A., Dominguez, F., John Baksi, A., O’Regan, D. P., Rosen, S. D., Prasad, S. K., Lara-Pezzi, E., Provencio, M., Lyon, A. R., Alonso-Pulpon, L., Cook, S. A., DePalma, S. R., Barton, P. J. R., Aplenc, R., Seidman, J. G., Ky, B., Ware, J. S., & Seidman, C. E.
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-07-02
Volume
140
Issue
1
Pages
31-41
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.118.037934
OpenAlex
W2938273454
Cited by
357
References
44
FWCI
25.59
Type
journal article
Language
en
Open access
hybrid

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CoChat. (2026). Citation check: Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy. https://app.cochat.ai/papers/10.1161/circulationaha.118.037934
The paper
Garcia-Pavia, P., Kim, Y., Restrepo-Cordoba, M. A., Lunde, I. G., Wakimoto, H., Smith, A. M., Toepfer, C. N., Getz, K., Gorham, J., Patel, P., Ito, K., Willcox, J. A., Arany, Z., Li, J., Owens, A. T., Govind, R., Nuñez, B., Mazaika, E., Bayes-Genis, A., . . . Seidman, C. E. (2019). Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy. Circulation. https://doi.org/10.1161/circulationaha.118.037934

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

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