Hypermethylation status of CDH1 gene in patients with diffuse gastric cancer

Ngô Diệu Hoa, Đặng Thị Ngọc Dung, Hán Minh Thủy, Tạ Thành Văn

Main Article Content

Abstract

Gastric cancer (GC), especially diffuse gastric cancer, is a common malignancy in the gastrointestinal tract with a poor prognosis, early-onset, often found late when cancer has metastasized. The CDH1 gene encodes the E-cadherin protein, which plays an important role in the adhesion between epithelial cells, and loses expression of the E-cadherin protein, leading to increased tumor progression and metastasis. CDH1 gene mutations are usually a point mutation and a heterozygous pattern, so a second hit mechanism is needed to manifest the disease. Hypermethylation in the CDH1 gene promoter region is considered the 'second hit' mechanism most commonly encountered with germline mutation causing diffuse gastric cancer. This study is to determined the hypermethylation of the CDH1 gene promoter region using methyl-specific PCR (MSP) after bisulfite transfer in 44 patients diagnosed with diffuse gastric cancer. The hypermethylation in the tumour region (86.4%) was higher than the hypermethylation in the normal region (59.1%); the difference was statistically significant (p = 0.034). The studies of hypermethylation between tumor regions and normal adjacent tissue, between  patients with cancer and normal people with standardization of sensitivity and specificity will create an indicator to assist in screenning the risk of spreading gastric cancer and open up a hopeful new direction in the target treatment of diffuse gastric cancer.

Article Details

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68(6):394-424.
2. Fock KM, Ang TL. Epidemiology of Helicobacter pylori infection and gastric cancer in Asia. Journal of gastroenterology and hepatology. 2010;25(3):479-486.
3. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392(6674):402-405.
4. Rashid H, Alam K, Afroze D, Yousuf A, Banday M, Kawoosa F. Hypermethylation Status of E-Cadherin Gene in Gastric Cancer Patients in a High Incidence Area. Asian Pacific journal of cancer prevention : APJCP. 2016;17(6):2757-2760.
5. Grady WM, Willis J, Guilford PJ, et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nature genetics. 2000;26(1):16-17.
6. Black MD, Kaneshiro R, Lai JI, Shimizu DM. Hereditary diffuse gastric cancer associated with E-cadherin germline mutation: a case report. Hawai'i journal of medicine & public health : a journal of Asia Pacific Medicine & Public Health. 2014;73(7):204-207.
7. Kague E, Thomazini CM, Pardini MI, Carvalho F, Leite CV, Pinheiro NA. Methylation status of CDH1 gene in samples of gastric mucous from Brazilian patients with chronic gastritis infected by Helicobacter pylori. Arq Gastroenterol. 2010;47(1):7-12.
8. Corso G, Roviello F, Paredes J, et al. Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2007;33(9):1061-1067.
9. Barber M, Murrell A, Ito Y, et al. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol. 2008;216(3):295-306.
10. Graziano 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. Annals of oncology : official journal of the European Society for Medical Oncology. 2004;15(3):489-492.
11. Kang GH, Lee HJ, Hwang KS, Lee S, Kim JH, Kim JS. Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation. The American journal of pathology. 2003;163(4):1551-1556.
12. Galmiche A, Rassow J, Doye A, et al. The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. Embo j. 2000;19(23):6361-6370.
13. Keates S, Keates AC, Warny M, Peek RM, Jr., Murray PG, Kelly CP. Differential activation of mitogen-activated protein kinases in AGS gastric epithelial cells by cag+ and cag- Helicobacter pylori. J Immunol. 1999;163(10):5552-5559.