Scientists say the results of a genome-wide study of methylation in gastric cancers has identified a subset of cancer, designated the CpG island methylator phenotype (CIMP), that is associated with widespread hypermethylation, relatively young patient age, and poor prognosis. A team led by Duke-NUS Graduate Medical School researchers in Singapore analyzed the genomes of 240 gastric cancers and 94 matched normal gastric tissues to determine cancer-related changes in methylation by measuring DNA methylation levels of 27,578 CpG sites.
Their results suggested that 25% of methylation alterations were significantly associated with changes in tumor gene expression, and while the majority were linked with epigenetically silenced genes, some were associated with switching genes on. Over 97% of these gene-silencing methylated CpG sites were within gene promotor regions.
The studies also identified long-range regions of epigenetic silencing (LRESs) within the CIMP subset, as well as long-range regions of tumor-specific hypomethylation that occurred primarily in the non-CIMP subset.
Interestingly, data from further analysis of the methylation patterns within the CIMP subset of tumors indicated that they may represent a clinically and biologically distinct subgroup of tumors. CIMP cell lines were susceptible to 5-aza-2′-deoxycytidine, a clinically approved demethylating drug.
"Our study does provide clarity in unambiguously demonstrating the presence of this subgroup and its features," comments Patrick Tan, M.D., lead author of the team’s published paper in Science Translational Medicine. "What's more, we are encouraged that there may be potential utility in testing the sensitivity of CIMP tumors to more potent DNA demethylating agents and possibly other epigenetic drugs … These findings move us forward, and additional work will focus on developing simple diagnostic tests to detect gastric cancer at earlier stages, plus drugs and drug targets that might exhibit high potency against different molecular subtypes of disease."
The researchers also note that H. pylori infection, one of the major identified risk factors for developing gastric cancer, itself causes alterations in the methylation of infected gastric cells. “Hence, the gastric cancer epigenetic landscape presented in this study should contribute to our understanding of how environmental (for example, H. pylori) and biological perturbations (for example, inflammation) can affect the genomes of gastric epithelial cells to enhance carcinogenic risk.”
The Duke-NUS investigators and colleagues in the U.S. and Singapore describe their work in a paper titled “Methylation Subtypes and Large-Scale Epigenetic Alterations in Gastric Cancer.”