De Novo Methylation in Cancer

Abstract

Epigenetics is the mechanism of gene expression regulation, which does not change DNA (deoxyribonucleic acid) sequences. Once CpG dinucleotides at the promotor regions are methylated, downstream genes are repressed. This process is essential for normal development and differentiation and is involved in cancer pathogenesis. Many tumour‐suppressor genes are repressed by aberrant promotor methylation. In addition, clinical cancer cases are classified into distinct subgroups based on DNA methylation accumulation patterns, suggesting that there might be a characteristic pathway of tumorigenesis in each subgroup. For example, the high‐methylation subgroup of colorectal cancer arises from sessile serrated adenomas that show similar high‐methylation accumulation and BRAF mutation. In gastric tumorigenesis, infection of pathogens, for example, Helicobacter pylori and Epstein‐Barr virus, can induce de novo methylation in gastric epithelial cells. Advances in the knowledge of DNA methylation accumulation patterns and the causal event of methylation induction lead to understanding molecular tumorigenic mechanisms.

Key Concepts

  • DNA methylation is mediated by DNA methyltransferases (DNMTs).
  • DNA demethylation is mediated by Ten‐eleven‐translocation (TET) family enzymes.
  • Tumour‐suppressor genes are frequently hypermethylated and silenced in cancer.
  • Clinical cancer cases are classified into distinct subgroups based on DNA methylation accumulation patterns.
  • Chronic inflammation may induce DNA methylation into epithelial cells.
  • Epstein‐Barr virus infection can induce DNA methylation into host cells.
  • Disruption of TET function through mutation of IDH or TET genes can cause aberrant DNA methylation.
  • Aberrant methylation might be used for cancer diagnosis and treatment.

Keywords: de novo DNA methylation; colorectal cancer; sessile serrated adenoma; gastric cancer; Helicobacter pylori; Epstein‐Barr virus; haematopoietic malignancies; glioblastoma; IDH1; TET2

Figure 1. De novo DNA methylation and demethylation of cytosine residue. Cytosine within the CpG dinucleotide is methylated at 5‐carbon position by DNA methyltransferases (DNMTs). The Ten‐eleven‐translocation (TET) family enzymes play key roles in active demethylation process converting 5‐methylcytosine to 5‐hydroximethylcytosine in an oxidative reaction, followed by producing 5‐formylcytosine and 5‐carbocylcytosine.
Figure 2. Gene silencing by promotor CpG island methylation. In the normal cell, active genes are known to be unmethylated at promotor CpG islands, while germ‐specific genes or repetitive sequences are methylated. In the cancer cell, hypomethylation occurs globally including repetitive sequences, while promotor CpG islands are frequently hypermethylated, leading to inactivation of downstream genes including tumour‐suppressor genes.
Figure 3. DNA methylation accumulation patterns with distinct tumour subtypes. Unsupervised clustering analysis using genome‐wide DNA methylation data can classify clinical cancer cases into distinct subgroups. Genes are also clustered into several gene groups that represent a specific methylation pattern for each cancer subgroup.
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Funata, Sayaka, Fukayama, Masashi, and Kaneda, Atsushi(Aug 2016) De Novo Methylation in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026465]