Methylation Subtypes and Large-Scale Epigenetic Alterations in Gastric Cancer

Abstract

Epigenetic alterations are fundamental hallmarks of cancer genomes. We surveyed the landscape of DNA methylation alterations in gastric cancer by analyzing genome-wide CG dinucleotide (CpG) methylation profiles of 240 gastric cancers (203 tumors and 37 cell lines) and 94 matched normal gastric tissues. Cancer-specific epigenetic alterations were observed in 44% of CpGs, comprising both tumor hyper- and hypomethylation. Twenty-five percent of the methylation alterations were significantly associated with changes in tumor gene expression. Whereas most methylation-expression correlations were negative, several positively correlated methylation-expression interactions were also observed, associated with CpG sites exhibiting atypical transcription start site distances and gene body localization. Methylation clustering of the tumors revealed a CpG island methylator phenotype (CIMP) subgroup associated with widespread hypermethylation, young patient age, and adverse patient outcome in a disease stage-independent manner. CIMP cell lines displayed sensitivity to 5-aza-2'-deoxycytidine, a clinically approved demethylating drug. We also identified long-range regions of epigenetic silencing (LRESs) in CIMP tumors. Combined analysis of the methylation, gene expression, and drug treatment data suggests that certain LRESs may silence specific genes within the region, rather than all genes. Finally, we discovered regions of long-range tumor hypomethylation, associated with increased chromosomal instability. Our results provide insights into the epigenetic impact of environmental and biological agents on gastric epithelial cells, which may contribute to cancer.

Plasticity of DNA methylation in a nerve injury model of pain

“…22 An increasing number of reports have further proposed that the methylome-transcriptome relationship cannot be represented by a simple model when considering large, high quality datasets. 10,21,23,36,37 In these studies, positive and negative correlations between methylation alterations and transcriptome changes were found only for a minority of CpGs. It was also suggested that the relationship depends on the CpG-content of the promoter region.…”

Nanoscale chromatin profiling of gastric adenocarcinoma reveals cancer-associated cryptic promoters and somatically acquired regulatory elements

“…Tumour suppressor genes such as CDH1 and RUNX3 are often silenced in primary GCs by promoter DNA methylation 12,13 , and changes in DNA methylation have also been associated with GC prognosis, chemosensitivity and drug resistance [14][15][16] . More recently, genome-wide studies have highlighted a role for both global and non-CpG island methylation in specific GC subtypes [17][18][19] , and exomesequencing studies have revealed that genes involved in chromatin modification such as ARID1A are frequently mutated in GC 2,4 . Currently however, the vast majority of epigenetic studies in GC have focused on characterizing patterns of aberrant DNA methylation.…”

Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia

“…Our data suggested a link between higher DNA methylation levels prior to decitabine treatment and better sensitivity to HMAs. In gastric cancers, Zouridis et al 36 reported the association of the CpG island methylator phenotype (CIMP) with better sensitivity to DNA methylation inhibitors. CIMP tumor type was identified in 68 of 203 primary gastric tumors and 7 of 17 gastric cancer cell lines, which displayed a unique feature of widespread hypermethylation at a global level compared to non-CIMP tumor type.…”