Epigenomics and ovarian carcinoma

Abstract

Ovarian cancer is the leading cause of death among gynecological cancers. It is now recognized that in addition to genetic alterations, epigenetic mechanisms, such as DNA methylation, histone modifications and nucleosome remodeling, play an important role in the development and progression of ovarian cancer by modulating chromatin structure, and gene and miRNA expression. Furthermore, epigenetic alterations have been recognized as useful tools for the development of novel biomarkers for diagnosis, prognosis, therapeutic prediction and monitoring of diseases. Moreover, new epigenetic therapies, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, have been found to be a potential therapeutic option, especially when used in combination with other agents. Here we discuss current developments in ovarian carcinoma epigenome research, the importance of the ovarian carcinoma epigenome for development of diagnostic and prognostic biomarkers, and the current epigenetic therapies used in ovarian cancer.

Figure 1. Two-hit hypothesis

According to the revised Knudson’s two-hit hypothesis, in the first hit one allele can be inactivated, either by localized mutation or promoter hypermethylation, leading to silencing of one allele of the affected gene. However, for full inactivation (complete silencing) of a target gene, a second hit is essential and can occur by LOH, mutation or promoter hypermethylation. Accumulation of multiple-gene alterations by genetic or epigenetic alterations and changes in the microenvironment leads to tumor development. LOH: Loss of heterozygosity. Adapted with permission from [2].

Figure 2. Epigenetic changes (DNA methylation, histone modifications and nucleosome remodeling) in normal and cancerous cells

Gene promoter regions are usually unmethylated in normal cells to maintain an euchromatic structure, which is the transcriptionally active form of chromatin, thus allowing gene expression (A). However, during cancer development, many of these genes become hypermethylated, changing the euchromatin structure to a more compact heterochromatin and repressing gene expression (B). TSS: Transcription start site.