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

Abstract

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.

New Insights in the Era of Clinical Biomarkers as Potential Predictors of Systemic Therapy-Induced Cardiotoxicity in Women with Breast Cancer: A Systematic Review

“…SLFN12 and IRF6 were hypermethylated and transcriptionally downregulated after the first cycle of chemotherapy compared to the baseline in all treatment groups ( IRF6 p = 0.8837 normal LVEF; IRF6 p = 0.8119 abnormal LVEF; SLNF12 p = 0.5718 normal LVEF; SLNF12 p = 0.8575 abnormal LVEF). Decrease in LVEF by >10% or LVEF < 50% compared to baseline Bauer et al, 2021 [ 293 ] High-throughput proteomic profiling using plasma samples Case/control pairs 1 and 2 Case/control pair 3 Validation study of 35 participants DOX plus cyclophosphamide followed by trastuzumab and paclitaxel. ECHO at baseline, after DOX treatment completion and every 3 months of trastuzumab treatment.…”

“…Bauer et al, 2021 [ 293 ], demonstrated that the methylation status of peripheral blood mononuclear cells (PBMCs) could predict the LVEF reduction after treatment with DOX in HER2-negative breast cancer patients. Specifically, a total of 14,883 differentially methylated CpGs were identified at baseline and were associated with a reduction in LVEF in response to DOX treatment.…”

Chemotherapy-induced acceleration of DNA methylation-based biological age in breast cancer

“…The following analyses were conducted using a publicly available dataset, which has previously been published [ 25 ]. Briefly, a total of 19 patients with breast cancer who underwent chemotherapy treatment at the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences were enrolled.…”

Precision Cardio-oncology: Update on Omics-Based Diagnostic Methods

“…DOX can lead to the downregulation of DNA methyltransferase 1 (DNMT1) enzyme activity, resulting in a decrease in DNA methylation [36]. For example, in one study, significantly differentially methylated regions were found in SLFN12, IRF6, and RNF39 genes and promoters in patients with LVEF abnormalities after DOX treatment [37].…”