DNA Methylation and Genetic Aberrations in Gastric Cancer

Abstract

<b><i>Background:</i></b> Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. GC is a pathologically and molecularly heterogeneous disease. DNA hypermethylation in promoter CpG islands causes silencing of tumor-suppressor genes and thus contributes to gastric carcinogenesis. In addition, various molecular aberrations, including aberrant chromatin structures, gene mutations, structural variants, and somatic copy number alterations, are involved in gastric carcinogenesis. <b><i>Summary:</i></b> Comprehensive DNA methylation analyses revealed multiple DNA methylation patterns in GCs and classified GC into distinct molecular subgroups: extremely high-methylation epigenotype uniquely observed in GC associated with Epstein-Barr virus (EBV), high-methylation epigenotype associated with microsatellite instability (MSI), and low-methylation epigenotype. In The Cancer Genome Atlas classification, EBV and MSI are extracted as independent subgroups of GC, whereas the remaining GCs are categorized into genomically stable (GS) and chromosomal instability (CIN) subgroups. EBV-positive GC, exhibiting the most extreme DNA hypermethylation in the whole human malignancies, frequently shows <i>CDKN2A</i> silencing, <i>PIK3CA</i> mutations, <i>PD-L1/2</i> overexpression, and lack of <i>TP53</i> mutations. MSI, exhibiting high DNA methylation, often has <i>MLH1</i> silencing and abundant gene mutations. GS is generally a diffuse-type GC and frequently shows <i>CDH1/RHOA</i> mutations or <i>CLDN18–ARHGAP</i> fusion. CIN is generally an intestinal-type GC and frequently has <i>TP53</i> mutations and genomic amplification of receptor tyrosine kinases. <b><i>Key Messages:</i></b> The frequency and targets of genetic aberrations vary depending on the epigenotype. Aberrations in the genome and epigenome are expected to synergistically interact and contribute to gastric carcinogenesis and comprehensive analyses of those in GCs may help elucidate the mechanism of carcinogenesis.