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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.

SUBMITTER: Garcia-Pavia P

PROVIDER: S-EPMC6613726 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.

Garcia-Pavia Pablo P Kim Yuri Y Restrepo-Cordoba Maria Alejandra MA Lunde Ida G IG Wakimoto Hiroko H Smith Amanda M AM Toepfer Christopher N CN Getz Kelly K Gorham Joshua J Patel Parth P Ito Kaoru K Willcox Jonathan A JA Arany Zoltan Z Li Jian J Owens Anjali T AT Govind Risha R Nuñez Beatriz B Mazaika Erica E Bayes-Genis Antoni A Walsh Roddy R Finkelman Brian B Lupon Josep J Whiffin Nicola N Serrano Isabel I Midwinter William W Wilk Alicja A Bardaji Alfredo A Ingold Nathan N Buchan Rachel R Tayal Upasana U Pascual-Figal Domingo A DA de Marvao Antonio A Ahmad Mian M Garcia-Pinilla Jose Manuel JM Pantazis Antonis A Dominguez Fernando F John Baksi A A O'Regan Declan P DP Rosen Stuart D SD Prasad Sanjay K SK Lara-Pezzi Enrique E Provencio Mariano M Lyon Alexander R AR Alonso-Pulpon Luis L Cook Stuart A SA DePalma Steven R SR Barton Paul J R PJR Aplenc Richard R Seidman Jonathan G JG Ky Bonnie B Ware James S JS Seidman Christine E CE

Circulation 20190416 1

<h4>Background</h4>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.<h4>Methods</h4>We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n ...[more]

PMID: 30987448

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Project description:Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiotherapy; n = 246) were compared with cardiotoxic-exposed survivors of European ancestry (n = 1,645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2-4 and grade 3-4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF (rs6689879*C: EF reduction = 4.2%; P = 2.8 × 10-8) in 246 survivors of African ancestry, which was successfully replicated in 1,645 survivors of European ancestry but with attenuated magnitude (EF reduction = 0.4%; P = 0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2-4 cardiomyopathy, the PHTF1 promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2-4 cardiomyopathy. PHTF1 was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry. SIGNIFICANCE: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry, and a novel locus at 1p13.2 is associated with therapy-related cardiomyopathy specifically in African-American survivors.See related commentary by Brown and Richard, p. 2272.

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Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.

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Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.

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