Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy

• DOI: 10.1161/circulationaha.118.037934
• Publication Date: 2019-04-16T09:00:11Z
• Authors: Pablo Garcia-Pavia; Yuri Kim; Maria Alejandra R...; Ida G. Lunde; Hiroko Wakimoto; Amanda M. Smith; Christopher N. To...; Kelly Getz; Joshua Gorham; Parth Patel; Kaoru Ito; Jonathan A. Willcox; Zoltan Arany; Jian Li; Anjali T. Owens; Risha Govind; Beatriz Nuñez; Erica Mazaika; Antoni Bayes-Genis; Roddy Walsh; Brian Finkelman; Josep Lupon; Nicola Whiffin; Isabel Serrano; William Midwinter; Alicja Wilk; Alfredo Bardaji; Nathan Ingold; Rachel Buchan; Upasana Tayal; Domingo A. Pascua...; Antonio de Marvao; Mian Ahmad; Jose Manuel Garci...; Antonis Pantazis; Fernando Dominguez; A. John Baksi; Declan P. O’Regan; Stuart D. Rosen; Sanjay K. Prasad; Enrique Lara-Pezzi; Mariano Provencio; Alexander R. Lyon; Luis Alonso-Pulpon; Stuart A. Cook; Steven R. DePalma; Paul J.R. Barton; Richard Aplenc; Jonathan G. Seidman; Bonnie Ky; James S. Ware; Christine E. Seidman
• Keywords: Cardiotoxicity

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 genes contribute Methods: studied 213 patients CCM from 3 cohorts: retrospectively recruited adults diverse cancers (n=99), prospectively phenotyped breast cancer (n=73), children acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified were sequenced. The prevalence of was compared between cohorts Genome Atlas participants (n=2053), healthy volunteers (n=445), an ancestry-matched reference population. Clinical characteristics outcomes assessed stratified by genotypes. A prevalent genotype modeled anthracycline-treated mice. Results: diagnosed 0.4 years after chemotherapy; 90% these received anthracyclines. Adult had risk factors similar the US Among prioritized more protein-altering than comparative ( P ≤1.98e–04). Titin-truncating (TTNtvs) predominated, occurring 7.5% versus 1.1% =7.36e–08), 0.7% =3.42e–06), 0.6% population =5.87e–14). who TTNtvs experienced heart failure atrial fibrillation =0.003) impaired myocardial recovery =0.03) those without. Consistent human data, TTNtv mice isolated cardiomyocytes showed sustained contractile dysfunction unlike wild-type =0.0004 <0.002, respectively). Conclusions: Unrecognized cardiomyopathy-associated particularly TTNtvs, increased adults, adverse cardiac events adults. Genotype, along chemotherapy dosage traditional factors, improves identification have at highest Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.