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Pregnancy-associated cardiomyopathy in survivors of childhood cancer.

ABSTRACT: Current information regarding pregnancy-associated cardiomyopathy among women treated for childhood cancer is insufficient to appropriately guide counseling and patient management. This study aims to characterize its prevalence within a large cohort of females exposed to cardiotoxic therapy.This is a retrospective cohort study of female cancer survivors treated at St. Jude Children's Research Hospital between 1963 and 2006, at least 5 years from diagnosis, ?13 years old at last follow-up, and with at least one successful pregnancy. Pregnancy-associated cardiomyopathy was defined as shortening fraction <28 % or ejection fraction <50 % or treatment for cardiomyopathy during or up to 5 months after completion of pregnancy.Among the 847 female cancer survivors with 1554 completed pregnancies, only 3 (0.3 %) developed pregnancy-associated cardiomyopathy and 40 developed non-pregnancy-associated cardiomyopathy either 5 months postpartum (n?=?14) or prior to pregnancy (n?=?26). Among those with cardiomyopathy prior to pregnancy (n?=?26), cardiac function deteriorated during pregnancy in eight patients (three patients with normalization of cardiac function prior to pregnancy, three with persistently abnormal cardiac function, and two for whom resolution of cardiomyopathy was unknown prior to pregnancy). Patients that developed cardiomyopathy received a higher median dose of anthracyclines compared to those that did not (321 versus 164 mg/m(2); p?

SUBMITTER: Hines MR

PROVIDER: S-EPMC4670599 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Pregnancy-associated cardiomyopathy in survivors of childhood cancer.

Hines Melissa R MR Mulrooney Daniel A DA Hudson Melissa M MM Ness Kirsten K KK Green Daniel M DM Howard Scott C SC Krasin Matthew M Metzger Monika L ML

Journal of cancer survivorship : research and practice 20150605 1

<h4>Purpose</h4>Current information regarding pregnancy-associated cardiomyopathy among women treated for childhood cancer is insufficient to appropriately guide counseling and patient management. This study aims to characterize its prevalence within a large cohort of females exposed to cardiotoxic therapy.<h4>Methods</h4>This is a retrospective cohort study of female cancer survivors treated at St. Jude Children's Research Hospital between 1963 and 2006, at least 5 years from diagnosis, ≥13 yea ...[more]

PMID: 26044903

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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.

Project description:Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

Dataset Information

Pregnancy-associated cardiomyopathy in survivors of childhood cancer.

Publications

Pregnancy-associated cardiomyopathy in survivors of childhood cancer.

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