Cancer genetics and epigenetics: two sides of the same coin?

Abstract

Epigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy.

Figure 1. The Crosstalk between Cancer Genetics and Epigenetics

The methylation of CpG sites located in DNMT3A exons (epigenetic alteration, represented as a black circle) potentially leads to genetic mutation in somatic cells by the hydrolytic deamination of 5mC to form a C to T transition mutation. Although it is not known whether DNMT3A directly methylates its own exon and the effect of this genetic mutation is not yet fully understood, it is possible that the C to T transition alters DNMT3A function and/or activity and thereby disrupts the epigenetic landscape. The Yin-Yang diagram emphasizes how epigenetic and genetic interactions are required to achieve perfect balance and suggests that disruption of the balance can lead to disease.

Figure 2. Genetic Mutations in Epigenetic Modifiers in Cancer

The drawing shows the interaction between epigenetic processes in specifying gene expression patterns. Recent whole exome sequencing studies show that mutations in the three classes of epigenetic modifiers is frequently observed in various types of cancers, further highlighting the crosstalk between genetics and epigenetics. Examples of some but not all of these mutations which are discussed in this review are shown. The mutations of epigenetic modifiers probably cause genome-wide epigenetic alterations in cancer but these have yet to be demonstrated in a genome wide scale. Understanding the relationship of genetic and the epigenetic changes in cancer will offer novel insights for cancer therapies.