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.