DNA methylation of multiple genes in gastric carcinoma: Association with histological type and CpG island methylator phenotype

Abstract

Hypermethylation of CpG islands is associated with silencing of various tumor suppressor genes. Recent studies on colorectal and gastric cancer have identified a CpG island methylator phenotype (CIMP), which involves the targeting of multiple genes by promoter hypermethylation. For determination of association between DNA methylation pattern or histological type and CIMP status in gastric carcinoma, CpG islands in the promoters of hMLH1 and CDH1 genes, CpG islands overlapping exon 1 of MGMT and p16INK4a genes, and a non-CpG island in exon 1 of the RAR-β β β β gene were studied. The presence of the CIMP was determined by monitoring five methylated in tumor (MINT) loci in 103 gastric carcinomas. Among the 103 gastric carcinomas, DNA hypermethylation was detected in the following frequencies: 14 (14%) for hMLH1, 26 (25%) for MGMT, 26 (25%) for p16 INK4a , 54 (52%) for CDH1, and 53 (52%) for RAR-β β β β. Forty-two (41%) of 103 gastric carcinomas were positive for the CIMP. CIMP and hypermethylation of p16INK4a gene were found more frequently in intestinal and diffuse-adherent types than in diffuse-scattered type (P = = = =0.013 and 0.017, respectively). In contrast, hypermethylation of the CDH1 and RAR-β β β β genes was more common in the diffusescattered type than in the other types (P = = = =0.008 and 0.007, respectively). In intestinal-and diffuse-adherent-type gastric carcinomas, we found significant associations between the presence of the CIMP and hypermethylation of several genes: hMLH1 (P = = = =0.006), p16 INK4a(P = = = =0.018), CDH1 (P = = = =0.024), and RAR-β β β β (P = = = =0.044). Our overall results suggest that in some intestinal-and diffuse-adherent-type gastric carcinomas, DNA hypermethylation affects non-specific gene promoters concordantly, at least in part, whereas in diffuse-scattered-type gastric carcinoma, DNA hypermethylation affects specific genes such as CDH1 and RAR-β β β β. lterations in DNA methylation patterns, such as hypermethylation of CpG islands, are common changes in human cancers. Hypermethylation of CpG islands in promoters is associated with silencing of various tumor suppressor genes.

DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis

“…Using different DNA methylation markers and different methodology, CpG island methylator phenotype was found to be associated with 'diffuse' histology in some reports 33,38 but not in others. 39,40 These controversial findings are most likely due to the use of differing DNA methylation marker panels as well as methods of analysis. In the present study, we analyzed 27 DNA methylation markers using the MethyLight technology and diffuse-type GC showed a significantly higher frequency of CpG island hypermethylation than intestinaltype GC, although the number of cases was limited.…”

Accumulation of DNA methylation is associated with tumor stage in gastric cancer

“…13 The presence or absence of CIMP and DNA methylation of 5 genes (hMLH1, MGMT, p16 INK4a , CDH1, and RAR-beta) was determined previously. 15 …”

“…13 Originally CIMP-positive GC was defined as a tumor with methylation at more than 3 loci methylated in tumors (MINT: MINT1, MINT2, MINT12, MINT25, and MINT31). 13 CIMP-positive GCs also tend to show DNA methylation of the p16 INK4a , 13 hMLH1, 15 and RIZ1 genes, 16 suggesting that CIMP is an important pathway involved in stomach carcinogenesis. However, limited numbers of genes have been shown to be associated with CIMP-positive GC, and the role of CIMP has not been clarified in detail.…”

The presence of JC virus in gastric carcinomas correlates with patient's age, intestinal histological type and aberrant methylation of tumor suppressor genes

“…Furthermore, concurrent promoter hypermethylation of multiple genes, which is termed descriptively as the 'CpG island methylator phenotype' (CIMP), was also described in gastric cancers. 7 Although, the epigenetic changes have been accepted as an important mechanism underlying tumor onset and progression, there are limited data related to factors inducing methylation. Recent studies have indicated the existence of a mechanistic linkage between DNA methylation and infectious agents.…”