Aberrant DNA methylation in contrast with mutations

Abstract

Aberrant DNA methylation is known as an important cause of human cancers, along with mutations. Although aberrant methylation was initially speculated to be similar to mutations, it is now recognized that methylation is quite unlike mutations. Whereas the number of mutations in individual cancer cells is estimated to be approximately 80, that of aberrant methylation of promoter CpG islands reaches several hundred to 1000. Although mutations of a specific gene are very few in non-cancerous (thus polyclonal) tissues (usually at 1 x 10(-5)/cell), aberrant methylation of a specific gene can be present up to several 10% of cells. Mutagenic chemicals and radiation are well-known inducers of mutations, whereas chronic inflammation is deeply involved in methylation induction. Although mutations are induced in mostly random genes, methylation is induced in specific genes depending on tissues and inducers. Methylation is potentially reversible, unlike mutations. These characteristics of methylation are opening up new fields of application and research.

Figure 1

Epigenetic field for cancerization and clonal selection in cancer. Normal epithelium consists of cells with little aberrant methylation. By exposure to inducers of methylation, specific genes are methylated in minor fractions of cells. A cancer develops from one of the cells that has already accumulated silencing of driver genes. From the viewpoint of assessment of an effect of an inducer, analysis of non‐cancerous tissues provides overall information on the genes methylated, and that of a cancer provides information on the genes stochastically methylated in the very precursor cell and driver genes.

Figure 2

Distribution patterns of methylation in non‐cancerous and cancer tissues. Methylation levels, which reflect fractions of cells with the methylation, were quantified in 66 paired samples of non‐cancerous and cancer tissues of gastric cancer patients (modified from Enomoto et al. ^{( 39 )}). They showed a unimodal distribution in non‐cancerous tissues, and a “bimodal” distribution, namely zero or positive, in cancer tissues. This finding supports the idea that methylation in a non‐cancerous tissue reflects events in many cells in the tissue whereas that in a cancer tissue mostly reflects only events in its single precursor cell.

Figure 3

Correlation between methylation level and cancer risk. Methylation levels of two marker genes (FLNc and HRASLS) were quantified in gastric mucosae of healthy individuals (healthy V), non‐cancerous gastric mucosae of patients with a single gastric cancer (single GC), and non‐cancerous gastric mucosae of patients with multiple gastric cancers (multiple GC) (modified from Nakajima et al. ^{( 47 )}). This showed that accumulation levels of specific genes in non‐cancerous gastric mucosae can correlate with gastric cancer risk. Taken together with the findings in other types of cancers, quantification of methylation levels in normal‐appearing tissues is a promising cancer risk marker that reflects one’s own life history.

Figure 4

Determinants of methylation destiny. Genes with RNA polymerase II (pol II), active or stalled, are resistant to DNA methylation, and genes with H3K27me3 are susceptible to DNA methylation. The presence of pol II is associated with the presence of active histone modifications, even if a gene is not actively transcribed. Open and closed circles show unmethylated and methylated CpG sites, respectively.