DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach

Abstract

BackgroundMethylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC.MethodsThe methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age, Helicobacter pylori status, tumor site, patient survival, microsatellite instability and BRAF and KRAS mutations.ResultsA total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, with HOXA5 and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy.ConclusionsHigh-throughput methylation analysis implicates genes involved in embryonic development and hedgehog signaling in gastric tumorigenesis. GC is comprised of two major methylation subtypes, with the highly methylated group showing some features consistent with a CpG island methylator phenotype.

DNA Methylation as a Molecular Biomarker in Gastric Cancer

“…CIMP-positive GCs [49,50]. An array-based genomewide methylation analysis of CIMP-positive GC showed significant enrichment of aberrant methylation in PRC target genes in CIMP-positive GC without EBV, whereas EBV-positive, CIMP-positive GC displayed extended methylation in both PRC target genes and non-PRC target genes.…”

“…future science group DNA methylation as a molecular biomarker in gastric cancer Review a better understanding of individual prognosis and risk and allows for improved clinical implementation [27,48,50,51]. Because epigenetic dysregulation of gene expression is reversible, one goal of the discovery of specific methylation changes would be the possibility of targeting epigenetic abnormalities for the treatment and prevention of GC.…”

High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing

“…6,9,10 CpG methylation is a central mechanism of epigenetic gene regulation, and occurs early in gastric cancer development, affecting genes known to have roles in gastric carcinogenesis such as MLH1, CDKN2A (p16), CDH1 (E-cadherin), RUNX3, COX-2, MGMT, and others. [11][12][13][14][15][16][17][18] Altered CpG methylation is already detected in mucosa with gastritis, is associated with chronic inflammation in response to H. pylori infection, and has been shown to be partially reversible after eradication of H. pylori infection. [19][20][21] In our study we used next-generation sequencing of bisulfite-treated DNA, which allows for sensitive quantification of the level of methylation at each individual CpG site present on the sequenced region.…”

Epstein-Barr Virus–Associated Gastric Carcinoma: The Americas’ Perspective

“…EBV-associated gastric cancer has been reported as the most extensive CpG island methylation at both human and viral genomes, being more extensive than any other tumor type from the TCGA network [14,21,57,58]. CpG island methylation is an epigenetic mechanism of gene expression regulation, affecting all cellular pathways [59].…”