Research on the Relationship between <i>CDH1</i> Gene Promoter Hypermethylation and Biological Behavior of Tumor in Human Gastric Carcinoma_West China Medical Journal

Authors：

 FENGNing ¹ , GAOHai-de ¹ , LIUWen-zhi ¹ , CHENXi ¹ ,  WUXiao-ting ²

1. Department of General Surgery, Dalian University Affiliated Hospital, Dalian, Liaoning 116001, P. R. China;
2. Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

WUXiao-ting, Email: wxt1@medmail.com.cn

Keywords：

DNA methylation; CDH1 gene promoter; E-cadherin; Methylation specific-polymerase chain reaction; Helicobacter pylori; Gastric cancer

DOI：

10.7507/1002-0179.20140012

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To determine the level of CDH1 gene promoter hypermethylation in human gastric carcinoma by establishing MS-PCR method, and analyze retrospectively the possible statistical relationship between CDH1 gene promoter hypermethylation in human gastric carcinoma and HP infection, tumor differentiation, invasion, lymph nodal and distant metastasis, respectively. Methods The bisulfite conversion MS-PCR method was adopted to examine the level of CDH1 gene promoter hypermethylation in 40 cases of human gastric carcinoma tissue collected between January 2008 and December 2009. The statistical relationship between CDH1 gene promoter hypermethylation in human gastric carcinoma and HP infection, tumor differentiation, invasion, lymph nodal and distant metastasis were examined respectively with SPSS statistical tools. Results The positive rate of CDH1 gene promoter hypermethylation in gastric carcinomas (67.5%) was higher than that in paired normal gastric mucosae (12.5%), and the difference was significant (P<0.05). In gastric carcinomas, the positive rate of CDH1 gene promoter hypermethylation in well differentiated or moderately differentiated groups (22.2%) was lower than that in poorly differentiated groups (80.6%), and the difference was significant (P<0.05). The positive rate of CDH1 gene promoter hypermethylation in HP positive groups (78.1%) was higher than that in HP negative groups (25.0%), and the difference was significant (P<0.05). Conclusion CDH1 gene promoter hypermethylation may play an important role in the process of tumor carcinogenesis in gastric carcinomas. Meanwhile, the CDH1 gene promoter hypermethylation may lead to poor differentiation in gastric carcinomas. CDH1 gene promoter hypermethylation is related to HP infection in the original gastric carcinomas, which shows that HP may get involved in the process of tumor suppressor gene methylation/inactivation and tumor development process.

Citation： FENGNing, GAOHai-de, LIUWen-zhi, CHENXi, WUXiao-ting. Research on the Relationship between CDH1 Gene Promoter Hypermethylation and Biological Behavior of Tumor in Human Gastric Carcinoma. West China Medical Journal, 2014, 29(1): 43-46. doi: 10.7507/1002-0179.20140012 Copy

1.	Graziano1 F, Arduini F, Ruzzo A, et al. 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[J]. Ann Oncol, 2004, 15(3):489-492.
2.	Monika Z, Ferreira AM, Czopek JP, et al. CDH1 gene promoter hypermethylation in gastric cancer:relationship to Goseki grading, microsatellite instability status, and EBV invasion[J]. Diagn Mol Pathol, 2006, 15(1):24-29.
3.	Giovanni C, Anna B, Daniele M, et al. CDH1 C-160A promoter polymorphism and gastric cancer risk[J]. Eur J Cancer Prev, 2009, 18(1):46-49.
4.	Gen T, Jing Y, Suna W, et al. E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas[J]. J Natl Cancer Inst, 2000, 92(7):569-573.
5.	Hatakeyama M. The role of Helicobacter pylori CagA in gastric carcinogenesis[J]. Int J Hematol, 2006, 84(4):301-308.
6.	Costa AC, Figueiredo C, Touati E. Pathogenesis of Helicobacter pylori infection[J]. Helicobacter, 2009, 14(Suppl 1):15-20.
7.	Lim JW, Kim H, Kim KH. Cell adhesion-related gene expression by Helicobacter pylori in gastric epithelial AGS cells[J]. Int J Biochem Cell Biol, 2003, 35(8):1284-1296.
8.	Grabiano F, Humar B, Guilford P. The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility:from the laboratory to clinical practice[J]. Ann Oncol, 2003, 14(12):1705-1713.
9.	Tamana M, Yoko M, Yasuhisa S, et al. E-cadherin gene promoter hypermethylation in H. pylori-induced enlarged fold astritis[J]. Helicobacter, 2007, 12(5):523-531.
10.	Carvalho B, Pinto M, Cirnes L, et al. Concurrent hypermethylation of gene promoters is associated with a MSI-H phenotype and diploidy in gastric carcinomas[J]. Eur J Cancer, 2003, 39(9):1222-1227.
11.	Lee TL, Leung WK, Chan MW, et al. Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma[J]. Clin Cancer Res, 2002, 8(6):1761-1766.
12.	Goseki N, Takizawa T, Koike M. Differences in the mode of the extension of gastric cancer classified by histological type:new histological classification of gastric carcinoma[J]. Gut, 1992, 33(5):606-612.
13.	Maekita T, Nakazawa K, Mihara M, et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk[J]. Clin Cancer Res, 2006, 12(3):989-995.
14.	Mayer B, Johnson JP, Leitl F, et al. E-cadherin expression in primary and metastatic gastric cancer:down-regulation correlates with cellular dedifferentiation and glandular disintegration[J]. Cancer Res, 1993, 53(7):1690-1695.
15.	Oka H, Shiozaki H, Kobayashi K, et al. Immunohistochemical evaluation of E-cadherin adhesion molecule expression in human gastric cancer[J]. Virchows Arch A Pathol Anat Histopathol, 1992, 421(2):149-156.
16.	Hirohashi S. Inactivation of the E-cadherin mediated cell adhesion system in human cancers[J]. Am J Pathol, 2008, 153(2):333-339.
17.	Becker KF, Atkinson MJ, Reich U, et al. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas[J]. Cancer Res, 2004, 54(14):3845-3852.
18.	Tamura G, Sakata K, Nishizuka S, et al. Inactivation of Ecadherin gene in primary gastric carcinomas and gastric carcinoma cell lines[J]. Jpn J Cancer Res, 2006, 87(11):1153-1159.
19.	Graff JR, Herman JG, Myohanen S, et al. Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation[J]. J Biol Chem, 2007, 272(35):22322-22329.
20.	Aggerholm A, Guldberg P, Hokland M, et al. Extensive intra- and interindividual heterogeneity of p15INK4B methylation in acute myeloid leukemia[J]. Cancer Res, 2009, 59(2):436-441.

1. Graziano1 F, Arduini F, Ruzzo A, et al. 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[J]. Ann Oncol, 2004, 15(3):489-492.
2. Monika Z, Ferreira AM, Czopek JP, et al. CDH1 gene promoter hypermethylation in gastric cancer:relationship to Goseki grading, microsatellite instability status, and EBV invasion[J]. Diagn Mol Pathol, 2006, 15(1):24-29.
3. Giovanni C, Anna B, Daniele M, et al. CDH1 C-160A promoter polymorphism and gastric cancer risk[J]. Eur J Cancer Prev, 2009, 18(1):46-49.
4. Gen T, Jing Y, Suna W, et al. E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas[J]. J Natl Cancer Inst, 2000, 92(7):569-573.
5. Hatakeyama M. The role of Helicobacter pylori CagA in gastric carcinogenesis[J]. Int J Hematol, 2006, 84(4):301-308.
6. Costa AC, Figueiredo C, Touati E. Pathogenesis of Helicobacter pylori infection[J]. Helicobacter, 2009, 14(Suppl 1):15-20.
7. Lim JW, Kim H, Kim KH. Cell adhesion-related gene expression by Helicobacter pylori in gastric epithelial AGS cells[J]. Int J Biochem Cell Biol, 2003, 35(8):1284-1296.
8. Grabiano F, Humar B, Guilford P. The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility:from the laboratory to clinical practice[J]. Ann Oncol, 2003, 14(12):1705-1713.
9. Tamana M, Yoko M, Yasuhisa S, et al. E-cadherin gene promoter hypermethylation in H. pylori-induced enlarged fold astritis[J]. Helicobacter, 2007, 12(5):523-531.
10. Carvalho B, Pinto M, Cirnes L, et al. Concurrent hypermethylation of gene promoters is associated with a MSI-H phenotype and diploidy in gastric carcinomas[J]. Eur J Cancer, 2003, 39(9):1222-1227.
11. Lee TL, Leung WK, Chan MW, et al. Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma[J]. Clin Cancer Res, 2002, 8(6):1761-1766.
12. Goseki N, Takizawa T, Koike M. Differences in the mode of the extension of gastric cancer classified by histological type:new histological classification of gastric carcinoma[J]. Gut, 1992, 33(5):606-612.
13. Maekita T, Nakazawa K, Mihara M, et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk[J]. Clin Cancer Res, 2006, 12(3):989-995.
14. Mayer B, Johnson JP, Leitl F, et al. E-cadherin expression in primary and metastatic gastric cancer:down-regulation correlates with cellular dedifferentiation and glandular disintegration[J]. Cancer Res, 1993, 53(7):1690-1695.
15. Oka H, Shiozaki H, Kobayashi K, et al. Immunohistochemical evaluation of E-cadherin adhesion molecule expression in human gastric cancer[J]. Virchows Arch A Pathol Anat Histopathol, 1992, 421(2):149-156.
16. Hirohashi S. Inactivation of the E-cadherin mediated cell adhesion system in human cancers[J]. Am J Pathol, 2008, 153(2):333-339.
17. Becker KF, Atkinson MJ, Reich U, et al. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas[J]. Cancer Res, 2004, 54(14):3845-3852.
18. Tamura G, Sakata K, Nishizuka S, et al. Inactivation of Ecadherin gene in primary gastric carcinomas and gastric carcinoma cell lines[J]. Jpn J Cancer Res, 2006, 87(11):1153-1159.
19. Graff JR, Herman JG, Myohanen S, et al. Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation[J]. J Biol Chem, 2007, 272(35):22322-22329.
20. Aggerholm A, Guldberg P, Hokland M, et al. Extensive intra- and interindividual heterogeneity of p15INK4B methylation in acute myeloid leukemia[J]. Cancer Res, 2009, 59(2):436-441.

West China Medical Journal

Research on the Relationship between CDH1 Gene Promoter Hypermethylation and Biological Behavior of Tumor in Human Gastric Carcinoma

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