Diet Folate, DNA Methylation and Polymorphisms in Methylenetetrahydrofolate Reductase in Association with the Susceptibility to Gastric Cancer

  • Gao, Shang (Department of Anthropotomy, School of Basic Medicine, Inner Mongolia Medical University) ;
  • Ding, Li-Hong (Department of Internal Medicine, Affiliated Hospital, Inner Mongolia Medical University) ;
  • Wang, Jian-Wei (Department of Anthropotomy, School of Basic Medicine, Inner Mongolia Medical University) ;
  • Li, Cun-Bao (Department of Biochemical and Molecular Biology, Affiliated Hospital, Inner Mongolia Medical University) ;
  • Wang, Zhao-Yang (Department of General Surgery, Affiliated Hospital, Inner Mongolia Medical University)
  • Published : 2013.01.31


Methylenetetrahydrofolate reductase (MTHFR) has been reported to be associated with DNA methylation, an epigenetic feature frequently found in gastric cancer. We conducted a case-control study to explore the association of MTHFR C677T polymorphisms with gastric cancer risk and its relation with the DNA methylation of COX-2, MGMT, and hMLH1 genes. Genotyping of P16, MGMT and HMLH1 was determined by methylation-specific PCR after sodium bisulfate modification of DNA, and genotyping of MTHFR C677T was conducted by TaqMan assays using the ABI Prism 7911HT Sequence Detection System. Folate intake was calculated with the aid of a questionnaire. Compared with the MTHFR 677CC genotype, the TT genotype was significantly associated with 2.08 fold risk of gastric cancer when adjusting for potential risk factors. Individuals who had an intake of folate above $310{\mu}g$/day showed protective effects against gastric cancer risk. The effect of MTHFR C677T polymorphisms on the risk of gastric cancer was modified by folate intake and methylation status of MGMT (P for interaction <0.05).


  1. Munoz N (1994). Is Helicobacter pylori a cause of gastric cancer? An appraisal of the seroepidemiological evidence. Cancer Epidemiol Biomarkers Prev, 3, 445-51.
  2. Perri F, Cotugno R, Piepoli A, et al (2007). Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication. Am J Gastroenterol, 102, 1361-71.
  3. Shen H, Xu Y, Zheng Y, et al (2001). Polymorphisms of 5, 10-methylenetetrahydrofolate reductase and risk of gastric cancer in a Chinese population: a case-control study. Int J Cancer, 5, 332-6.
  4. Taylor DN, Blaser MJ (1991). The epidemiology of Helicobacter pylori infection. Epidemiol Rev, 13, 42-59.
  5. Vollset SE, Igland J, Jenab M, et al (2007). The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev, 16, 2416-24.
  6. Wang J, Sasco AJ, Fu C, et al (2008). Aberrant DNA methylation of P16, MGMT, and hMLH1 genes in combination with MTHFR C677T genetic polymorphism in esophageal squamous cell carcinoma. Cancer Epidemiol Biomark Prev, 17, 118-25.
  7. Zacho J, Yazdanyar S, Bojesen SE, et al (2011). Hyperhomocysteinemia, methylenetetrahydrofolate reductase c.677C>T polymorphism and risk of cancer: cross-sectional and prospective studies and meta-analyses of 75,000 cases and 93,000 controls. Int J Cancer, 128, 644-52.
  8. Zhao P, Lin F, Li Z, et al (2011). Folate intake, methylenetetrahydrofolate reductase polymorphisms, and risk of esophageal cancer. Asian Pac J Cancer Prev, 12, 2019-23.
  9. Zuniga-Noriega JR, Velazco-Campos Mdel R, Aguirre-Rodriguez A, et al (2007). C677T polymorphism of the MTHFR gene and the risk of developing distal gastric cancer in a Mexican population. Rev Gastroenterol Mex, 72, 355-8.
  10. Cui LH, Shin MH, Kweon SS, Kim HN, et al (2010). Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer in a Korean population. BMC Cancer, 10, 236.
  11. Das PM, Singal R (2004). DNA methylation and cancer. J Clin Oncol, 22, 4632-42.
  12. DE Cassia Carvalho Barbosa R, DA Costa DM, Cordeiro DE, et al (2012). Interaction of MTHFR C677T and A1298C, and MTR A2756G Gene Polymorphisms in Breast Cancer Risk in a Population in Northeast Brazil. Anticancer Res, 32, 4805-11.
  13. Eichholzer M, Luthy J, Moser U, et al (2001). Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence. Swiss Med Wkly, 131, 539-49.
  14. Galvan-Portillo MV, Cantoral A, Onate-Ocana LF, et al (2009): Gastric cancer in relation to the intake of nutrients involved in onecarbon metabolism among MTHFR 677 TT carriers. Eur J Nutr, 48, 269-76.
  15. Gius D, Bradbury CM, Sun L, et al (2005). The epigenome as a molecular marker and target. Cancer, 104, 1789-93.
  16. International Agency for Research on Cancer (2008). Globocan 2008: Stomach Cancer incidence, Mortality and Prevalence Worldwide in 2008. IARC.
  17. Issa JP (2004). CpG island methylator phenotype in cancer. Nat Rev Cancer, 4, 988-93.
  18. Jernal A, Siegel R, Ward E, Murray T, et al (2007). Cancer statistics, 2007. CA Cancer J Clin, 57, 43-66.
  19. Jing C, Huang Z, Duan Y, et al (2012). Folate intake, methylenetetrahydrofolate reductase polymorphisms in association with the prognosis of esophageal squamous cell carcinoma. Asian Pac J Cancer Prev, 13, 647-51.
  20. La Vecchia C, Negri E, Pelucchi C, Franceschi S (2002). Dietary folate and colorectal cancer. Int J Cancer, 102, 545-7.
  21. Lee KH, Lee JS, Nam JH, et al (2011). Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence. Langenbecks Arch Surg, 396, 1017-26.
  22. Mason JB (2009). Folate, cancer risk, and the Greek god, Proteus: A tale of two chameleons. Nutr Rev, 67, 206-12.
  23. Momparler RL, Bovenzi V (2000). DNA methylation and cancer. J Cell Physiol, 183, 145-54.<145::AID-JCP1>3.0.CO;2-V
  24. Nakai K, Mitomi H, Alkam Y, et al (2012). Predictive value of MGMT, hMLH1, hMSH2 and BRCA1 protein expression for pathological complete response to neoadjuvant chemotherapy in basal-like breast cancer patients. Cancer Chemother Pharmacol, 69, 923-30.
  25. Qin JM, Wang XM, Chen B, et al (2008). Study on the ingestion of folate and polymorphism of MTHFR C677T with esophageal cancer in Xinjiang Kazakh. Zhonghua Liu Xing Bing Xue Za Zhi, 29, 30-3.
  26. Saberi S, Zendehdel K, Jahangiri S, et al (2012). Impact of Methylenetetrahydrofolate Reductase C677T Polymorphism on the Risk of Gastric Cancer and Its Interaction with Helicobacter pylori Infection. Iran Biomed J, 16, 179-84.
  27. Chen HTK, Graubard BI, Heineman EF, et al (2002). Nutrient intakes and adenocarcinoma of the esophagus and distal stomach. Nutr Cancer, 42, 33-40.
  28. Chen J, Huang ZJ, Duan YQ, et al (2012). Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in combination with MTHFR C677T Genetic Polymorphism and Folate Intake in Esophageal Squamous Cell Carcinoma. Asian Pac J Cancer Prev, 13, 5303-6.

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