Identification of DNA methylation changes associated with human gastric cancer

Abstract

BackgroundEpigenetic alteration of gene expression is a common event in human cancer. DNA methylation is a well-known epigenetic process, but verifying the exact nature of epigenetic changes associated with cancer remains difficult.MethodsWe profiled the methylome of human gastric cancer tissue at 50-bp resolution using a methylated DNA enrichment technique (methylated CpG island recovery assay) in combination with a genome analyzer and a new normalization algorithm.ResultsWe were able to gain a comprehensive view of promoters with various CpG densities, including CpG Islands (CGIs), transcript bodies, and various repeat classes. We found that gastric cancer was associated with hypermethylation of 5' CGIs and the 5'-end of coding exons as well as hypomethylation of repeat elements, such as short interspersed nuclear elements and the composite element SVA. Hypermethylation of 5' CGIs was significantly correlated with downregulation of associated genes, such as those in the HOX and histone gene families. We also discovered long-range epigenetic silencing (LRES) regions in gastric cancer tissue and identified several hypermethylated genes (MDM2, DYRK2, and LYZ) within these regions. The methylation status of CGIs and gene annotation elements in metastatic lymph nodes was intermediate between normal and cancerous tissue, indicating that methylation of specific genes is gradually increased in cancerous tissue.ConclusionsOur findings will provide valuable data for future analysis of CpG methylation patterns, useful markers for the diagnosis of stomach cancer, as well as a new analysis method for clinical epigenomics investigations.

Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity

“…This finding confirms the close association between MSI and the CpG island methylator phenotype (CIMP) already described in gastric and colorectal adenocarcinomas (Toyota et al 1999, Samowitz et al 2005. In these sites, genome-wide methylation studies have confirmed that CIMP and MSI are a homogeneous subset of cancers harboring aberrant DNA methylation mechanisms (Park et al 2011, Hinoue et al 2012, Xu et al 2012. Fourthly, we demonstrated that the wellknown relationship reported in colorectal adenocarcinomas between MSI phenotype and BRAF V600E mutation (Boland et al 2009) is also found in MSI-NEC/MANECs of the colonrectum.…”

Deciphering the Epigenetic Code: An Overview of DNA Methylation Analysis Methods

“…MIRAseq (46) MeDIP-seq (16), MethylCap-seq (using MeCP2) (8), MBD-isolated genome sequencing (49) follows more or less similar protocols (except affinity enrichment itself). As an example, two of the reported workflows are summarized in Figure 8 (46,50). Although similar in approach, enrichment methods target different compartments of the genome.…”

“…Affinity enrichment coupled to high-throughput sequencing. These workflows are based on protocols reported by (42) and (46) and may differ from other reports. A portion of DNA is kept aside (input control), which is used to compare relative enrichment of methylated fraction in precipitated samples.…”

Biological Consequences of Priming Phosphorylation in Cancer Development

“…With some exceptions [35][36][37], DYRK1A and DYRK2 have been characterized as a potential tumor suppressor [38][39][40][41][42][43][44][45][46][47][48][49]. In contrast, DYRK1B (also known MIRK), closely related to DYRK1A, have been characterized as a positive regulator of cancer cell survival [50][51][52][53][54][55][56][57][58][59][60][61].…”