Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

Abstract

Abstract.The main obstacle to the successful treatment of ovarian cancer is the development of drug resistance to combined chemotherapy. Among all the factors associated with drug resistance, DNA methylation apparently plays a critical role. In this study, we performed an integrative analysis of the 26 DNA-methylated genes associated with drug resistance in ovarian cancer, and the genes were further evaluated by comprehensive bioinformatics analysis including gene/protein interaction, biological process enrichment and annotation. The results from the protein interaction analyses revealed that at least 20 of these 26 methylated genes are present in the protein interaction network, indicating that they interact with each other, have a correlation in function, and may participate as a whole in the regulation of ovarian cancer drug resistance. There is a direct interaction between the phosphatase and tensin homolog (PTEN) gene and at least half of the other genes, indicating that PTEN may possess core regulatory functions among these genes. Biological process enrichment and annotation demonstrated that most of these methylated genes were significantly associated with apoptosis, which is possibly an essential way for these genes to be involved in the regulation of multidrug resistance in ovarian cancer. In addition, a comprehensive analysis of clinical factors revealed that the methylation level of genes that are associated with the regulation of drug resistance in ovarian cancer was significantly correlated with the prognosis of ovarian cancer. Overall, this study preliminarily explains the potential correlation between the genes with DNA methylation and drug resistance in ovarian cancer. This finding has significance for our understanding of the regulation of resistant ovarian cancer by methylated genes, the treatment of ovarian cancer, and improvement of the prognosis of ovarian cancer. IntroductionOvarian cancer is a malignant tumour posing a serious threat to women's health. As the main type of ovarian cancer, ovarian epithelial carcinoma accounts for 85-90% of all ovarian cancers. The mortality rate of ovarian epithelial carcinoma ranks first among all female reproductive tract malignancies. Approximately 70% of ovarian cancer patients are in the late stage when diagnosed. Most of these tumours easily develop drug resistance in the course of post-surgery chemotherapy; therefore, the therapeutic effect is greatly reduced, leading to a survival rate of just 30% for ovarian cancer (1). Therefore, multidrug resistance is the main cause of ovarian cancer chemotherapy failure. Studies have demonstrated that multidrug resistance is the result of multiple genes or proteins and a multistep process, or cross-reactivity of multiple factors. Multidrug resistance involves several different regulatory mechanisms, and epigenetic regulation is one of the significant regulatory mechanisms in the development of ovarian cancer multidrug resistance (2). Epigenetic modification is a heritable change in gene expression without a DNA...

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