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Epigenome analysis of doxorubicin-induced cardiotoxicity before and after treatemt of breast cancer patients

ABSTRACT: This study aimed to determine whether methylation signature of peripheral blood mononuclear cells (PBMCs) prior to the start of the first cycle of DOX-based chemotherapy could predict the risk of cardiotoxicity in breast cancer patients as well as determine if DOX treatment changed methlation profiles. The Illumina Infinium 450 Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 450k CpGs PBMCs samples before and after treatment. Samples included 10 samples from patients with normal ejection fraction after DOX treatment, 9 samples from patients with abnormal ejection fraction (indicative of cardiotoxicity) after DOX treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178887 | GEO | 2021/12/29

REPOSITORIES: GEO

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Project description:TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

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Epigenome analysis of doxorubicin-induced cardiotoxicity before and after treatemt of breast cancer patients

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