Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1 in the gastric epithelium

BMC Gastroenterology

Tomiyasu Arisawa²  Tomoyuki Shibata¹  Nobuyuki Toshikuni²  Masakatsu Nakamura²  Toshimi Otsuka²  Kazuhiro Matsunaga²  Ranji Hayashi²  Yasuhiro Matsue²  Takahiro Minato²  Hisakazu Shiroeda²  Tomomitsu Tahara¹  Tomoe Nomura² 

[1] Department of Gatroenterology, Fujita Health University, School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan;Department of Gastroenterology, Kanazawa Medical University, 1-1, Daigaku, Uchinada-machi, Ishikawa, 920-0293, Japan

关键词: Aberrant DNA methylation;    Genetic polymorphism;    HRH2;   

Others  :  858253
DOI  :  10.1186/1471-230X-13-1

 received in 2012-06-12, accepted in 2012-12-27,  发布年份 2013

【 摘 要 】

Background

Aberrant 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.

Methods

Non 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.

Results

Methylation 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.

Conclusions

Our results suggest that rs2607474 GG homozygote confers a significantly increased risk for age- and inflammation-related DAPK and CDH1 methylation.

【 授权许可】

   
2013 Nomura et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin 2005, 55:74-108.
• [2]Kamangar F, Dores GM, Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006, 24:2137-2150.
• [3]Esteller M, Corn PG, Baylin SB, Herman JG: A gene hypermethylation profile of human cancer. Cancer Res 2001, 61:3225-3229.
• [4]Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, Yonemura J, Maeda Y, Maruyama N, Kamano T, Kamiya Y, Fujita H, Nakagawa Y, Nagasaka M, Iwata M, Hirata I, Arisawa T: Increased number of CpG island hypermethylation in tumor suppressor genes of Non-neoplastic gastric mucosa correlates with higher risk of gastric cancer. Digestion 2010, 82:27-36.
• [5]Kass SU, Pruss D, Wolffe AP: How does DNA methylation repress transcription? Trends Genet 1997, 13:444-449.
• [6]Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB: Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 1994, 4:536-540.
• [7]Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP: Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 1998, 23:5489-5494.
• [8]Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA: Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 2001, 61:3573-3577.
• [9]Sato F, Harpaz N, Shibata D, Xu Y, Yin J, Mori Y, Zou TT, Wang S, Desai K, Leytin A, Selaru FM, Abraham JM, Meltzer SJ: Hypermethylation of the p14 (ARF) gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res 2002, 62:1148-1151.
• [10]Bian YS, Osterheld MC, Fontolliet C, Bosman FT, Benhattar J: p16 Inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett’s esophagus. Gastroenterology 2002, 122:1113-1121.
• [11]Maekita T, Nakazawa K, Mihara M, Nakajima T, Yanaoka K, Iguchi M, Arii K, Kaneda A, Tsukamoto T, Tatematsu M, Tamura G, Saito D, Sugimura T, Ichinose M, Ushijima T: High levels of aberrant DNA methylation in helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res 2006, 12:989-995.
• [12]Tahara T, Arisawa T, Sibata T, Wang FY, Nakamura M, Sakata M, Nagasaka M, Takagi T, Kamiya Y, Fujita H, Nakamura M, Hasegawa S, Iwata M, Takahama K, Watanabe M, Hirata I, Nakano H: Risk prediction of gastric cancer by analysis of aberrant DNA methylation in non-neoplastic gastric epithelium. Digestion 2007, 75:54-61.
• [13]Kang GH, Lee S, Lim JS, Jung HY: Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis. Lab Invest 2003, 83:635-641.
• [14]Tahara T, Arisawa T, Shibata T, Nakamura M, Yoshioka D, Okubo M, Maruyama N, Kamano T, Kamiya Y, Fujita H, Nakagawa Y, Nagasaka M, Iwata M, Takahama K, Watanabe M, Yamashita H, Hirata I: Increased number of methylated CpG islands correlates with helicobacter pylori infection, histological and serological severity of chronic gastritis. Eur J Gastroenterol Hepatol 2009, 21:613-619.
• [15]Rangachari PK: Histamine: mercurial messenger in the gut. Am J Physiol 1992, 262:G1-G13.
• [16]Black J, Duncan W, Durant D: Definition and antagonism of histamine H2-receptors. Nature 1972, 236:385-390.
• [17]Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH: Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987, 28:1120-1127.
• [18]Bodger K, Crabtree JE: Helicobacter pylori and gastric inflammation. Br Med Bull 1998, 54:139-150.
• [19]Mancama D, Arranz MJ, Munro J, Osborne S, Makoff A, Collier D, Kerwin R: Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response. Neurosci Lett 2002, 333:207-211.
• [20]Garcia-Martin E, Ayuso P, Luengo A, Martinez C, Agundez JAG: Genetic variability of histamine receptors in patients with Parkinson’s disease. BMC Med Genet 2008, 9:15.
• [21]Dixon MF, Genta RM, Yardley JH, Correa P: Classification and grading of gastritis: the updated Sydney system. Am J Surg Pathol 1996, 20:1161-1181.
• [22]Katzenellenbogen RA, Baylin SB, Herman JG: Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 1999, 93:4347-4353.
• [23]Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996, 93:9821-9826.
• [24]Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, Fujita H, Yoshioka D, Arima Y, Okubo M, Hirata I, Nakano H: The relationship between helicobacter pylori infection and promoter polymorphism of the Nrf2 gene in chronic gastritis. Int J Mol Med 2007, 19:143-148.
• [25]Arisawa T, Tahara T, Ozaki K, Matsue Y, Minato T, Yamada H, Nomura T, Hayashi R, Matsunaga K, Fukumura A, Nakamura M, Toshikuni N, Shiroeda H, Shibata T: Association between common genetic variant of HRH2 and gastric cancer risk in Japanese population. Int J Oncolin press
• [26]Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kamiya Y, Fujita H, Hasegawa S, Takagi T, Wang FY, Hirata I, Nakano H: A polymorphism of microRNA 27a genome region is associated with the development of gastric mucosal atrophy in Japanese male subjects. Dis Dig Sci 2007, 52:1691-1697.
• [27]Hu XC, Loo WT, Chow LW: E-cadherin promoter methylation can regulate its expression in invasive ductal breast cancer tissue in Chinese woman. Life Sci 2002, 71:1397-1404.
• [28]Graziano F, Arduini F, Ruzzo A, Mandolesi A, Bearzi I, Silva R, Muretto P, Testa E, Mari D, Magnani M, Scartozzi M, Cascinu S: Combined analysis of E-cadherin gene (CDH1) promoter hypermethylation and E-cadherin protein expression in patients with gastric cancer: implications for treatment with demethylating drugs. Ann Oncol 2004, 15:489-492.
• [29]Bai T, Tanaka T, Yukawa K, Maeda M, Umesaki N: Reduced expression of death-associated protein kinase in human uterine and ovarian carcinoma cells. Oncol Rep 2004, 11:661-665.
• [30]Kim WS, Son HJ, Park JO, Song SY, Park C: Promoter methylation and down-regulation of DAPK is associated with gastric atrophy. Int J Mol Med 2003, 12:827-830.
• [31]Kaise M, Yamasaki T, Yonezawa J, Miwa J, Ohta Y, Tajiri H: CpG island hypermethylation of tumor-suppressor genes in H. Pylori - infected non-neoplastic gastric mucosa is linked with gastric cancer risk. Helicobacter 2008, 13:35-41.
• [32]Tahara T, Arisawa T: Potential usefulness of DNA methylation as a risk marker for digestive cancer. Expert Rev Mol Diagn 2012, 12:489-497.
• [33]Ito C, Morisset S, Krebs MO, Olié JP, Lôo H, Poirier MF, Lannfelt L, Schwartz JC, Arrang JM: Histamine H2 receptor gene variants: lack of association with schizophrenia. Mol Psychiatry 2000, 5:159-164.
• [34]Correa P: Human gastric carcinogenesis: a multistep and multifactorial process. First American cancer society award lecture on cancer epidemiology and prevention. Cancer Res 1992, 52:6735-6740.
• [35]Kuipers EJ, Uyterlinde AM, Peña AS, Hazenberg HJ, Bloemena E, Lindeman J, Klinkenberg-Knol EC, Meuwissen SG: Increase of helicobacter pylori-associated corpus gastritis during acid suppressive therapy: implications for long-term safety. Am J Gastroenterol 1995, 90:1401-1406.
• [36]Kuipers EJ, Lundell L, Klinkenberg-Knol EC, Havu N, Festen HP, Liedman B, Lamers CB, Jansen JB, Dalenback J, Snel P, Nelis GF, Meuwissen SG: Atrophic gastritis and helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996, 334:1018-1022.
• [37]Berstad AE, Hatlebakk JG, Maartmann-Moe H, Berstad A, Brandtzaeg P: Helicobacter pylori gastritis and epithelial cell proliferation in patients with reflux esophagitis after treatment with lansoprazole. Gut 1997, 41:740-747.
• [38]Poynter D, Selway SA: Neuroendocrine cell hyperplasia and neuroendocrine carcinoma of the rodent Fundic stomach. Mutat Res 1991, 248:303-319.
• [39]Brenna E, Swarts HG, Klaassen CH, de Pont JJ, Waldum HL: Evaluation of the trophic effect of longterm treatment with the histamine H2 receptor antagonist loxtidine on rat oxyntic mucosa by differential counting of dispersed cells. Gut 1994, 35:1547-1550.
• [40]Hunyady B, Zolyomi A, Czimmer J, Mózsik G, Kozicz T, Buzás E, Tanaka S, Ichikawa A, Nagy A, Palkovits M, Falus A: Expanded parietal cell pool in transgenic mice unable to synthesize histamine. Scand J Gastroenterol 2003, 38:133-140.