RT Journal Article
T1 Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
A1 Garcia-Pavia, Pablo
A1 Kim, Yuri
A1 Restrepo-Cordoba, Maria Alejandra
A1 Lunde, Ida G
A1 Wakimoto, Hiroko
A1 Smith, Amanda M
A1 Toepfer, Christopher N
A1 Getz, Kelly
A1 Gorham, Joshua
A1 Patel, Parth
A1 Ito, Kaoru
A1 Willcox, Jonathan A
A1 Arany, Zoltan
A1 Li, Jian
A1 Owens, Anjali T
A1 Govind, Risha
A1 Nuñez, Beatriz
A1 Mazaika, Erica
A1 Bayes-Genis, Antoni
A1 Walsh, Roddy
A1 Finkelman, Brian
A1 Lupon, Josep
A1 Whiffin, Nicola
A1 Serrano, Isabel
A1 Midwinter, William
A1 Wilk, Alicja
A1 Bardaji, Alfredo
A1 Ingold, Nathan
A1 Buchan, Rachel
A1 Tayal, Upasana
A1 Pascual-Figal, Domingo A
A1 de Marvao, Antonio
A1 Ahmad, Mian
A1 Garcia-Pinilla, Jose Manuel
A1 Pantazis, Antonis
A1 Dominguez, Fernando
A1 John Baksi, A
A1 O'Regan, Declan P
A1 Rosen, Stuart D
A1 Prasad, Sanjay K
A1 Lara-Pezzi, Enrique
A1 Provencio, Mariano
A1 Lyon, Alexander R
A1 Alonso-Pulpon, Luis
A1 Cook, Stuart A
A1 DePalma, Steven R
A1 Barton, Paul J R
A1 Aplenc, Richard
A1 Seidman, Jonathan G
A1 Ky, Bonnie
A1 Ware, James S
A1 Seidman, Christine E
K1 cardiomyopathies
K1 drug therapy
K1 genetics
K1 medical oncology
K1 titin
AB 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. 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. 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 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. URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.
YR 2019
FD 2019-04-16
LK http://hdl.handle.net/10668/13834
UL http://hdl.handle.net/10668/13834
LA en
DS RISalud
RD Apr 17, 2025