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@article{Garcia-Pavia:2019:10.1161/CIRCULATIONAHA.118.037934,
author = {Garcia-Pavia, P and Kim, Y and Restrepo-Cordoba, MA and Lunde, IG and Wakimoto, H and Smith, AM and Toepfer, CN and Getz, K and Gorham, J and Patel, P and Ito, K and Willcox, JA and Arany, Z and Li, J and Owens, AT and Govind, R and Nuñez, B and Mazaika, E and Bayes-Genis, A and Walsh, R and Finkelman, B and Lupon, J and Whiffin, N and Serrano, I and Midwinter, W and Wilk, A and Bardaji, A and Ingold, N and Buchan, R and Tayal, U and Pascual-Figal, DA and de, Marvao A and Ahmad, M and Garcia-Pinilla, JM and Pantazis, A and Dominguez, F and John, Baksi A and O'Regan, DP and Rosen, SD and Prasad, SK and Lara-Pezzi, E and Provencio, M and Lyon, AR and Alonso-Pulpon, L and Cook, SA and DePalma, SR and Barton, PJR and Aplenc, R and Seidman, JG and Ky, B and Ware, JS and Seidman, CE},
doi = {10.1161/CIRCULATIONAHA.118.037934},
journal = {Circulation},
pages = {31--41},
title = {Genetic variants associated with cancer therapy-induced cardiomyopathy},
url = {http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037934},
volume = {140},
year = {2019}
}

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TY  - JOUR
AB  - BackgroundCancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and pre-existing cardiovascular disorders. These parametersincompletely account for substantial inter-individual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM.MethodsWe studied 213 CCM patients from three cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped breast cancer adults (n=73) and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including nine pre-specified genes were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas (TCGA) participants(n=2053), healthy volunteers(n=445), and ancestry-matchedreference population. Clinical characteristics and outcomes were assessed, stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice.ResultsCCM was diagnosed 0.4-9 years after chemotherapy; 90% of these patients received anthracyclines. Adult CCM patients had cardiovascular risk factors similar to the U.S. population. Among nine prioritized genes CCM patients had more rare protein-altering variants than comparative cohorts (p≤1.98e-04). Titin-truncating variants (TTNtv) predominated, occurring in 7.5% CCM patients versus 1.1% TCGA participants (p=7.36e-08), 0.7% healthy volunteers (p=3.42e-06), and 0.6% reference population (p=5.87e-14). Adult CCM patients with TTNtv 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 wildtype (p=0.0004 and p<0.002, respectively).ConclusionsUnrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtv, increased the risk for CCM in children and adults, and adverse cardiac events
AU  - Garcia-Pavia,P
AU  - Kim,Y
AU  - Restrepo-Cordoba,MA
AU  - Lunde,IG
AU  - Wakimoto,H
AU  - Smith,AM
AU  - Toepfer,CN
AU  - Getz,K
AU  - Gorham,J
AU  - Patel,P
AU  - Ito,K
AU  - Willcox,JA
AU  - Arany,Z
AU  - Li,J
AU  - Owens,AT
AU  - Govind,R
AU  - Nuñez,B
AU  - Mazaika,E
AU  - Bayes-Genis,A
AU  - Walsh,R
AU  - Finkelman,B
AU  - Lupon,J
AU  - Whiffin,N
AU  - Serrano,I
AU  - Midwinter,W
AU  - Wilk,A
AU  - Bardaji,A
AU  - Ingold,N
AU  - Buchan,R
AU  - Tayal,U
AU  - Pascual-Figal,DA
AU  - de,Marvao A
AU  - Ahmad,M
AU  - Garcia-Pinilla,JM
AU  - Pantazis,A
AU  - Dominguez,F
AU  - John,Baksi A
AU  - O'Regan,DP
AU  - Rosen,SD
AU  - Prasad,SK
AU  - Lara-Pezzi,E
AU  - Provencio,M
AU  - Lyon,AR
AU  - Alonso-Pulpon,L
AU  - Cook,SA
AU  - DePalma,SR
AU  - Barton,PJR
AU  - Aplenc,R
AU  - Seidman,JG
AU  - Ky,B
AU  - Ware,JS
AU  - Seidman,CE
DO  - 10.1161/CIRCULATIONAHA.118.037934
EP  - 41
PY  - 2019///
SN  - 0009-7322
SP  - 31
TI  - Genetic variants associated with cancer therapy-induced cardiomyopathy
T2  - Circulation
UR  - http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037934
UR  - http://hdl.handle.net/10044/1/68726
VL  - 140
ER  -

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