Hypermethylation Status of E-Cadherin Gene in Gastric Cancer Patients in a High Incidence Area

  • Rashid, Haroon (Department of General and Minimal Invasive Surgery, Sher-I-Kashmir Institute of Medical Sciences) ;
  • Alam, Khursheed (Department of General and Minimal Invasive Surgery, Sher-I-Kashmir Institute of Medical Sciences) ;
  • Afroze, Dil (Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences) ;
  • Yousuf, Adfar (Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences) ;
  • Banday, Manzoor (Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences) ;
  • Kawoosa, Fizalah (Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences)
  • Published : 2016.06.01


Gastric cancer (GC) is the fourth most prevalant cancer and the second leading cause of cancer-related mortality worldwide. As in other cancers gastric carcinogenesis is multifactorial involving environmental, genetic and epigenetic components. Epigenetic silencing due to hypermethylation of tumour suppressor genes is one of the key events in gastric carcinogenesis. This study was aimed to analyse the hypermethylation status of the E-Cadherin (CDH1) gene promoter in GCs in the ethnic Kashmiri population. In this study a total of 80 GC patients were recruited. Hypermethylation in tumour tissue was detected by methylation specific PCR (MS-PCR). Hypermethylation of CDH1 promoter was observed in 52 (65%) of gastric carcinoma cases which was significantly much higher than adjacent normal tissue [$p{\leq}0.0001$]. Further the frequency of CDH1 promoter methylation was significantly different with intestinal and diffuse types of gastric cancer [55.7% vs 82.1%; p<0.05]. Moreover females and cases with lymph node invasion had higher frequencies of CDH1 hypermethylation [$P{\leq}0.05$]. Thus the current data indicate a vital role of epigenetic alteration of CDH1 in the causation and development of gastric cancer, particularly of diffuse type, in our population.


  1. Bussemakers MJ, van Bokhoven A, Mees SG, Kemler R, Schalken JA (1993). Molecular cloning and characterization of the human E-cadherin cDNA. Mol Biol Rep, 17, 123-128. https://doi.org/10.1007/BF00996219
  2. Choi IS, Wu TT (2005). Epigenetic alterations in gastric Carcinogenesis. Cell Res, 15, 247-54. https://doi.org/10.1038/sj.cr.7290293
  3. Correa P (1992). Human gastric carcinogenesis, a multistep and multifactorial process-first American cancer society award lecture on cancer epidemiology and prevention. Cancer Res, 52, 6735-40.
  4. Du W, Wang S, Zhou Q, et al (2013). ADAMTS9 is a functional tumor suppressor through inhibiting AKT/mTOR pathway and associated with poor survival in gastric cancer. Oncogene, 32, 3319-28. https://doi.org/10.1038/onc.2012.359
  5. Enokida H, Shiina H, Urakami S et al (2005). Ethnic grouprelated differences in CpG hypermethylation of the GSTP1gene promoter among African-American, Caucasian and Asian patientswith prostate cancer. Int J Cancer, 116, 174-81. https://doi.org/10.1002/ijc.21017
  6. Galanter JM , Christopher RG, Sam SO, et al (2015). Methylation analysis reveals fundamental differences between ethnicity and genetic ancestry. Bio Rxiv.
  7. Guan Z, Zhang J, Song S, Dai D (2013). Promoter methylation and expression of TIMP3 gene in gastric cancer. Diagn Pathol, 8, 1-6.
  8. Graziano F, Arduini F, Ruzzo A, et al(2004). Prognostic analysis of E-cadherin gene promoter hypermethylation in patients with surgically resected, node-positive, diffuse gastric cancer. Clin Cancer Res, 10, 2784-9. https://doi.org/10.1158/1078-0432.CCR-03-0320
  9. Hu X, Sui X, Li L, et al (2013). Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol, 229, 62-73. https://doi.org/10.1002/path.4093
  10. Humar B, Blair V, Charlton A, et al (2009). E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man. Cancer Res, 69, 2050-6.
  11. Jemal A, Bray, Center M, Ferlay, Ward E, Forman D (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  12. Kang GH, Lee HJ, Hwang KS, et al (2003). Aberrant CpG Island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation. Am J Pathol, 163, 1551-6. https://doi.org/10.1016/S0002-9440(10)63511-0
  13. Karayiannakis AJ, Syrigos KN, Chatzigianni E, et al (1998). Aberrant E-cadherin expression associated with loss of differentiation and advanced stage in human pancreatic cancer. Anticancer Res, 18, 4177-80.
  14. Lee TL, Leung WK, Chan MW et al (2002). Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma. Clin Cancer Res, 8, 1761-6.
  15. Machado JC, Oliveira C, Carvalho R, et al (2001). E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma. Oncogene, 20, 1525-8. https://doi.org/10.1038/sj.onc.1204234
  16. Oliveira C, Sousa S, Pinheiro H, et al (2009). Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression. Gastroenterol, 136, 2137-48. https://doi.org/10.1053/j.gastro.2009.02.065
  17. Pandith AA, Siddiqi MA (2012). Burden of cancers in the valley of Kashmir, 5 year epidemiological study reveals a different scenario. Tumor Biol, 33, 1629-37. https://doi.org/10.1007/s13277-012-0418-z
  18. Parkin DM, Bray F, Ferlay J, Pisani P(2005) . Global cancer statistics 2002. CA Cancer J Clin, 55, 74-108. https://doi.org/10.3322/canjclin.55.2.74
  19. Rao V, Ganesh B (1998). Estimate of cancer incidence in India in 1991. Indian J Cancer, 35, 10-18.
  20. Siegel R, Ma J, Zou Z, Jemal A(2014). Cancer statistics, 2014. CA Cancer J Clin, 64, 9-29. https://doi.org/10.3322/caac.21208
  21. Tahara T, Shibata T, Arisawa T, et al (2010). CpG island promoter methylation (CIHM) status of tumor suppressor genes correlates with morphological appearances of gastric cancer. Anticancer Res, 30, 239-244.
  22. Takeichi M (1990). Cadherins: a molecular family important in selective cell-cell adhesion. Annu Rev Biochem, 59, 237-52. https://doi.org/10.1146/annurev.bi.59.070190.001321
  23. Van RF (2014). Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat Rev Cancer, 14, 121-34. https://doi.org/10.1038/nrc3647
  24. Wang K, Yuen ST, Xu J, et al (2014). Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nature Genetics, 46, 573-82. https://doi.org/10.1038/ng.2983
  25. Wani M, Afroze D, Makhdoomi M, et al (2012). Promoter Methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir Valley. Asian Pac J Cancer Prev, 13, 4177-418. https://doi.org/10.7314/APJCP.2012.13.8.4177
  26. Yi Kim D, Kyoon Joo J, Kyu Park Y, et al (2007). E-cadherin expression in early gastric carcinoma and correlation with lymph node metastasis. J Surg Oncol, 96, 429-35 . https://doi.org/10.1002/jso.20732
  27. Yoo TH, Ryu BK, Lee MG, Chi SG (2013). CD81 is a candidate tumor suppressor gene in human gastric cancer. Cell Oncol, 36, 141-53. https://doi.org/10.1007/s13402-012-0119-z
  28. Yousuf A, Bhat MY, Pandith AA, et al (2014). MGMT gene silencing by promoter hypermethylation in gastric cancer in a high incidence area. Cell Oncol, 37, 245-52. https://doi.org/10.1007/s13402-014-0179-3
  29. Zhang KL, Sun Y, Li Y, et al (2008). Increased frequency of CpG island methylator phenotype and CDH1 methylation in a gastric cancer high-risk region of china. Transl Oncol 1, 28-35. https://doi.org/10.1593/tlo.07103
  30. Zheng Z, Pan J, Chu B, et al (1999). Down¬regulation and abnormal expression of E-cadherin and beta-catenin in nasopharyngeal carcinoma: close association with advanced disease stage and lymph node metastasis. Hum Pathol, 30, 458-66. https://doi.org/10.1016/S0046-8177(99)90123-5
  31. Zhu AL, Sonnenberg A (2012). Is gastric cancer again rising? J Clin Gastroenterol, 46, 804-6. https://doi.org/10.1097/MCG.0b013e3182604254
  32. Zouridis H, Deng N, Ivanova T, et al (2012). Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci Transl Med, 4, 156ra140.