Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

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.

Keywords: cardiomyopathies; drug therapy; genetics; medical oncology; titin.

Figures

Figure.

Persistent cardiac dysfunction in Ttntv/+ mice after anthracycline treatment. A, Untreated Ttntv/+ mice have left ventricular function comparable with wild-type (WT) mice., Intraperitoneal doxorubicin (5mg/kg) was administered (arrows) to WT and Ttntv/+ mice (n=15 per genotype) in 3 successive weekly doses (cumulative dose=45 mg/m2). Serial echocardiograms showed persistent significantly depressed systolic function (mean fractional shortening ±SD) in Ttntv/+ in comparison with WT mice (P=0.0004). B, Isolated cardiomyocytes (n≥52 per group) were studied 12 weeks after initial doxorubicin injection. Cardiomyocytes from doxorubicin-treated Ttntv/+ mice had significantly depressed contractility (P<0.002) in comparison with cardiomyocytes from doxorubicin-treated WT mice or untreated mice. NS indicates not significant.