Introduction

In addition to genomic changes in cancer, there is also selection for aberrant epigenetic changes that do not involve an alteration in DNA sequence but result in a stable alteration in gene expression. Indeed, epigenetic, rather than genetic, changes may be a more prevalent driver of tumour development and progression. Such epigenetic mechanisms include DNA methylation, post-translational modifications of histones, nucleosomal positioning and non-coding RNAs. All types of gynaecological cancer show widespread aberrant epigenetic changes, leading to changes in expression of genes involved in all the hallmarks of cancer and of genes involved in how tumours will respond to chemotherapy. Such epimutations can be reversed using small-molecule inhibitors of maintenance of the epigenetic state. Tumour biomarkers and an understanding of the mechanisms of epigenetic regulation will be key to identifying novel epigenetic therapies, and epigenetic biomarkers also have potential to impact on clinical management in gynaecological cancer. Currently, there is much interest in the potential to target epigenetic mechanisms in tumour stem cells as a means of eradicating subpopulations of cells that may lead to tumour recurrence and drug resistance. However, there remain many obstacles to the implementation of these epigenetic approaches in clinical practice.

DNA methylation and gene transcription

One of the most widely studied epigenetic changes is DNA methylation occurring in mammalian DNA at CpG dinucleotides where the hydrogen bond at the 5 position of cytosine becomes methylated (Figure 3.1). DNA methylation is catalysed by a group of enzymes called the DNA methyltransferases (DNMTs).