Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1in the gastric epithelium

Tomoe Nomura,Kazuhiro Matsunaga,Tomiyasu Arisawa,Tomomitsu Tahara,Tomoyuki Shibata,Toshimi Otsuka,Masakatsu Nakamura,Yasuhiro Matsue,Nobuyuki Toshikuni,Takahiro Minato,Ranji Hayashi,Hisakazu Shiroeda

doi:10.1186/1471-230x-13-1

Tomoe Nomura, Kazuhiro Matsunaga + Show 10 more

Open Access

https://doi.org/10.1186/1471-230x-13-1

Copy DOI

Abstract

BackgroundAberrant methylation patterns in CpG island are known to be influential in gene silencing. Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. We report an investigation into the effect of HRH2 promoter polymorphism (rs2607474 G > A) on the methylation of DAPK and CDH1.MethodsNon cancerous gastric mucosa samples were obtained from 115 subjects with gastric cancer (GC) and 412 non-cancer subjects (non-GC). Methylation status of genes was determined by MSP. The genotyping of rs2607474 was performed by PCR-SSCP.ResultsMethylation of DAPK and CDH1 was observed in 296 and 246 subjects, respectively. The frequency of CDH1 methylation in the subjects with GC was significantly lower in cancer lesion than in non cancerous mucosa, whereas that of DAPK methylation was not different. The allelic distribution of rs2607474 was 401GG, 119GA and 7AA. The GG homozygote was associated with a significantly increased risk for methylation of both DAPK and CDH1 (p < 0.0001 and p = 0.0009, respectively). In the non-GC subjects or more than 60 years of age, GG homozygote was more closely associated with both DAPK and CDH1 methylation. However, this genotype did not show an increased risk for the development of methylation of both genes in patients with GC. In H. pylori negative subjects, GG homozygote showed an increased risk for the methylation of both DAPK and CDH1 (p = 0.0074 and p = 0.0016, respectively), whereas this genotype was associated with an increased risk for the development of DAPK methylation in H. pylori positive subjects (p = 0.0018). In addition, in subjects older than 60 years of age, atrophy and metaplasia scores were significantly higher in the GG homozygote (p = 0.011 and p = 0.039, respectively) and a significant correlation was observed between age and atrophy or metaplasia.ConclusionsOur results suggest that rs2607474 GG homozygote confers a significantly increased risk for age- and inflammation-related DAPK and CDH1 methylation.

Highlights

Aberrant methylation patterns in CpG island are known to be influential in gene silencing
death-associated protein kinase (DAPK), CDH1and cyclin-dependent kinase inhibitor 2A (CDKN2A) are known to be frequently methylated in non-neoplastic gastric mucosa and this methylation is linked to age, H. pylori infection, histological degree of gastritis, and gastric cancer [11,13,14]
We investigated the relationship between Histamine H2 receptor gene (HRH2) promoter polymorphism and DNA methylation of DAPK and E-cadherin gene (CDH1) in noncancerous gastric epithelium

Summary

Introduction

Aberrant methylation patterns in CpG island are known to be influential in gene silencing. Several cancers, including gastric tumors, show methylation of multiple genes including E-cadherin (CDH1), death-associated protein kinase (DAPK) and cyclin-dependent kinase inhibitor 2A (CDKN2A) [3,4]. Methylation of promoter CpG islands leads to DNA structural changes and, consequentially, gene inactivation [5]. It has been postulated that methylation of CpG island is induced by Helicobacter pylori (H. pylori) infection in non-cancerous mucosa [11,12] and considered as the precancerous conditions in gastric carcinogenesis [13]. DAPK, CDH1and CDKN2A are known to be frequently methylated in non-neoplastic gastric mucosa and this methylation is linked to age, H. pylori infection, histological degree of gastritis, and gastric cancer [11,13,14]

Methods

Results

Discussion

Conclusion