Genome-Wide DNA Methylation Signatures Predict the Early Asymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer.

Michael Bauer,Valentina Todorova,Joseph Su,Ping-Ching Hsu,Matthew Plotkin,Jeanne Wei,Annjanette Stone,Weleetka Carter,Issam Makhoul

doi:10.3390/cancers13246291

Abstract

Simple SummaryThis study examined whether the DNA methylation state of peripheral blood mononuclear cells (PBMCs) could predict cardiotoxicity caused by doxorubicin (DOX)-based chemotherapy in breast cancer patients. The results showed a significant difference in the pattern of DNA methylation of PBMCs associated with a risk of cardiotoxicity. These preliminary findings have the potential to further the goal of personalized medicine and tailor the treatment of breast cancer with DOX-based chemotherapy to reduce the toxicity to the heart.Chemotherapy with doxorubicin (DOX) may cause unpredictable cardiotoxicity. This study aimed to determine whether the methylation signature of peripheral blood mononuclear cells (PBMCs) prior to and after the first cycle of DOX-based chemotherapy could predict the risk of cardiotoxicity in breast cancer patients. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) by >10%. DNA methylation of PBMCs from 9 patients with abnormal LVEF and 10 patients with normal LVEF were examined using Infinium HumanMethylation450 BeadChip. We have identified 14,883 differentially methylated CpGs at baseline and 18,718 CpGs after the first cycle of chemotherapy, which significantly correlated with LVEF status. Significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SLFN12, IRF6 and RNF39 in patients with abnormal LVEF. The pathway analysis found enrichment for regulation of transcription, mRNA splicing, pathways in cancer and ErbB2/4 signaling. The preliminary results from this study showed that the DNA methylation profile of PBMCs may predict the risk of DOX-induced cardiotoxicity prior to chemotherapy. Further studies with larger cohorts of patients are needed to confirm these findings.

Highlights

Doxorubicin (DOX) is an anthracycline antibiotic commonly used for treatment of breast and other malignancies [1]
A two-tailed t-test of the delta in left ventricular ejection fraction (LVEF) before and after treatment between the two groups was significant with a p-value ≤ 0.05 (Supplemental Table S5)
We investigated the potential of methylation state to shed light on predicting cardiotoxicity of DOX-based chemotherapy in breast cancer

Summary

Introduction

Doxorubicin (DOX) is an anthracycline antibiotic commonly used for treatment of breast and other malignancies [1]. A major and yet unpredictable side effect of DOX is the development of cardiomyopathy that may lead to irreversible congestive heart failure [2]. DOX-induced cardiotoxicity is exponentially dose-dependent beginning with the first dose with asymptomatic myocardial injury and may progress to irreversible symptomatic heart failure (HF) years after treatment [3,4]. 10% of patients treated with DOX develop cardiac complications up to 10 years after cessation of chemotherapy [7]. The damaging effects of DOX on the heart often are not detected until years after cessation of the chemotherapy, it is important to identify patients at risk before or at the early doses of chemotherapy [8,9,10]

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