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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:Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anti-cancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for explore the inter-individual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intra- individual variability of iPSC-CM-related assays and presented a practical approach for using donor-specific iPSC-CMs to predict personalized doxorubicin (DOX)-induced cardiotoxicity (DIC) prior to chemotherapy. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intra-individual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice, and largely replicated the reported mechanisms of DIC. By categorizing iPSC-CMs into DOX-resistant and DOX-sensitive cell lines based on their phenotypic reactions to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we assessed the limitations of the model for identification of potential genetic/molecular biomarker and pinpointed a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. We also discussed the selection of DOX dose and exposure duration for inter-individual variability of DIC assessment. Our results support the utility of donor-specific iPSC-CMs in assessing inter-individual difference and enabling personalized cardiotoxicity prediction. Further studies will encompass a large panel of donor-specific iPSC-CMs to investigate the role of the DND1 and known DIC genetic variants, and to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.