Anthracycline-induced cardiomyopathy in childhood cancer survivors is associated with gene signatures of mitochondrial dysfunction—a COG ALTE03N1 report

BACKGROUND: Anthracycline-induced cardiomyopathy is a leading cause of morbidity and mortality in survivors of childhood cancer. The mitochondrion is a key mediator of the cytotoxic effects of anthracycline treatment and mitochondrial dysfunction is a hallmark of cardiomyopathy and heart failure. We sought to evaluate whether mitochondrial processes differ between anthracycline-exposed childhood cancer survivors who developed cardiomyopathy versus those who did not. METHODS: Peripheral blood was collected from 40 childhood cancer survivors who developed cardiomyopathy (cases) and 64 matched survivors who did not (controls). From these samples, gene expression was determined by RNA-Sequencing. Following bioinformatic processing, differential gene expression at the mRNA-level between cases and controls was determined. Human MitoCarta3.0, was utilized to determine if genes involved in mitochondrial processes were enriched for differential expression, and to identify differentially regulated mitochondrial pathways at the mRNA-level. RESULTS: 900 genes were identified as differentially expressed at the mRNA-level. The odds of a gene being differentially expressed were 2.43 times greater if it encodes for a protein that localizes to the mitochondria. Mitochondrial processes that were enriched for differentially expressed genes at the mRNA-level included electron transport chain complexes; reactive oxygen species metabolism; apoptosis, mitophagy, and autophagy; mitochondrial ribosome; mitochondrial transport and chaperones; and heme synthesis and processing. Additionally, we observed that a measure of pro-apoptotic balance (BAX to BCL-2 gene expression at the mRNA-level) was highest in severe cardiomyopathy, intermediate in mild cardiomyopathy, and lowest in survivors without cardiomyopathy. CONCLUSIONS: We observed substantial evidence that the expression of genes involved in mitochondrial processes differs in childhood cancer survivors who develop cardiomyopathy versus those who do not.