Genetic Predisposing Variants Associated with Cancer Therapy-Induced Cardiomyopathy

Background: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and pre-existing cardiovascular disorders. These parameters incompletely account for substantial inter-individual susceptibility to CCM. We therefore hypothesised that rare variants in cardiomyopathy genes might contribute to CCM. Methods:  Using a case-control study, we analysed 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). Control cohorts included 2053 cancer patients participating in The Cancer Genome Project (TCGA), 445 healthy volunteers, and the Genome Aggregation Database (gnomAD). We compared the frequency of rare variants in cardiomyopathy genes, including nine pre-specified genes between groups. Clinical characteristics and outcomes were assessed, stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. Findings: CCM was diagnosed 0.4-9 years after chemotherapy; 90% of patients received anthracyclines. 12.2% of CCM patients exhibited rare protein-altering variants among the nine prioritized genes versus 3.4% of healthy volunteers (p=5.16e-05). 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=4.04e-06), and gnomAD population (p=6.09e-09). Adult CCM patients with TTNtv versus those without experienced more heart failure and atrial fibrillation (p=0.003). 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). Interpretation: Rare variants in cardiomyopathy-associated genes, particularly TTNtv, increase the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype improves identification of cancer patients at highest risk for CCM. Funding Statement: Instituto de Salud Carlos III, John S LaDue Memorial Fellowship at Harvard Medical School, Wellcome Trust, UK Medical Research Council, NIHR Biomedical Research Unit, Foundation Leducq, British Heart Foundation, National Institutes of Health and the Howard Hughes Medical Institute. Declaration of Interests: CES and JGS are founders and own shares in Myokardia Inc., a startup company that is developing therapeutics that target the sarcomere. Myokardia had no involvement in this study. Ethics Approval Statement: Research protocols were reviewed and approved by institutional ethics board at each participating site [for Cohorts A,B, and C (human patients)]. Mice study: Protocols were reviewed and approved by the Institutional Animal Care and Use Committee at Harvard Medical School (Boston, MA).