The Methylenetetrahydrofolate Reductase C677T Polymorphism Influences Risk of Esophageal Cancer in Chinese

  • Qu, Hong-Hong (Department of Epidemiology and Biostatistics, College of Public Health) ;
  • Cui, Li-Hong (Digestive System Department, PLA Navy General Hospital) ;
  • Wang, Ke (Department of Epidemiology and Biostatistics, College of Public Health) ;
  • Wang, Peng (Department of Epidemiology and Biostatistics, College of Public Health) ;
  • Song, Chun-Hua (Department of Epidemiology and Biostatistics, College of Public Health) ;
  • Wang, Kai-Juan (Department of Epidemiology and Biostatistics, College of Public Health) ;
  • Zhang, Jian-Ying (Department of Epidemiology and Biostatistics, College of Public Health) ;
  • Dai, Li-Ping (Department of Epidemiology and Biostatistics, College of Public Health)
  • Published : 2013.05.30


Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism. This study with 381 esophageal cancer patients and 432 healthy controls was conducted to examine the association of MTHFR C677T and A1298C polymorphisms with susceptibility to esophageal cancer (EC) in a Chinese population. Compared with the CC genotype of MTHFR C677T, subjects carrying homozygote TT and variant genotypes (CT+TT) demonstrated reduced risk of EC with adjusted ORs (95% CI) of 0.44 (0.28-0.71) and 0.57 (0.37-0.88), respectively. However, no association was found between the MTHFR A1298C polymorphism and the risk of EC. Comparing to haplotype CA, haplotypes TA and TC could reduce the susceptibility to EC with adjusted ORs (95% CI) of 0.61(0.47-0.79) and 0.06 (0.01-0.43), respectively. In conclusion, the present study suggested that the MTHFR C677T polymorphism can markedly influence the risk of EC in Chinese.


  1. Bailey LB, Gregory JF 3rd (1999). Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr, 129, 919-22.
  2. Banerjee RV, Matthews RG (1990). Cobalamin-dependent methionine synthase. FASEB J, 4, 1450-9.
  3. Boccia S, Gianfagna F, Persiani R, et al (2007). Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population. Biomarkers, 12, 635-44.
  4. Chen J, Giovannucci E, Kelsey K, et al (1996). A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res, 56, 4862-4.
  5. Choi SW, Mason JB (2000). Folate and carcinogenesis: an integrated scheme. J Nutr, 130, 129-32.
  6. Friso S, Choi SW, Girelli D, et al (2002). A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. P Natl Acad Sci USA, 99, 5606-56.
  7. Frosst P, Blom HJ, Milos R, et al (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet, 10, 111-3.
  8. Gao S, Ding LH, Wang JW, et al (2013). Diet folate, DNA methylation and polymorphisms in methylenetetrahydrofolate reductase in association with the susceptibility to gastric cancer. Asian Pac J Cancer Prev, 14, 299-302.
  9. Gao YT, McLaughlin JK, Blot WJ, et al (1994). Risk factors for esophageal cancer in Shanghai, China. I. Role of cigarette smoking and alcohol drinking. Int J Cancer, 58, 192-6.
  10. Giovannucci E, Rimm EB, Ascherio A, et al (1995). Alcohol, low-methionine--low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst, 87, 265-73.
  11. Gao YT, McLaughlin JK, Gridley G, et al (1994). Risk factors for esophageal cancer in Shanghai, China. II. Role of diet and nutrients. Int J Cancer, 58, 197-202.
  12. Hahn LW, Ritchie MD, Moore JH (2003). Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics, 19, 376-82.
  13. Huang Y, Han S, Li Y, et al (2007). Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: a meta-analysis. J Hum Genet, 52, 73-85.
  14. Islami F, Boffetta P, Ren JS, et al (2009). High-temperature beverages and foods and esophageal cancer risk-A systematic review. Int J Cancer, 125, 491-524.
  15. Jaskiewicz K, Marasas WF, Lazarus C, et al (1988). Association of esophageal cytological abnormalities with vitamin and lipotrope deficiencies in populations at risk for esophageal cancer. Anticancer Res, 8, 711-5.
  16. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  17. Kureshi N, Ghaffar S, Siddiqui S, et al (2004). Head and neck cancer susceptibility: a genetic marker in the methylenetetrahydrofolate reductase gene. ORL J Otorhinolaryngol Relat Spec, 66, 241-5.
  18. Larsson SC, Giovannucci E, Wolk A (2006). Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology, 131, 1271-83.
  19. Ma J, Stampfer MJ, Giovannucci E, et al (1997). Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res, 57, 1098-102.
  20. Matsuo K, Hamajima N, Suzuki R, et al (2004). Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma. Am J Hematol, 77, 351-7.
  21. Matsuo K, Suzuki R, Hamajima N, et al (2001). Association between polymorphisms of folate- and methionine metabolizing enzymes and susceptibility to malignant lymphoma. Blood, 97, 3205-9.
  22. Prasad MP, Krishna TP, Pasricha S, et al (1992). Esophageal cancer and diet-a case-control study. Nutr Cancer, 18, 85-93.
  23. Ritchie MD, Hahn LW, Roodi N, et al (2001). Multifactordimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet, 69, 138-47.
  24. Skibola CF, Smith MT, Kane E, et al (1999). Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. P Natl Acad Sci USA, 96, 12810-5.
  25. Slattery ML, Potter JD, Samowitz W, et al (1999). Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev, 8, 513-8.
  26. Song C, Xing D, Tan W, et al (2001). Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Res, 61, 3272-5.
  27. Stern LL, Mason JB, Selhub J, et al (2000). Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev, 9, 849-53.
  28. Stolzenberg-Solomon RZ, Qiao YL, Abnet CC, et al (2003). Esophageal and gastric cardia cancer risk and folate- and vitamin B(12)-related polymorphisms in Linxian, China. Cancer Epidemiol Biomarkers Prev, 12, 1222-6.
  29. Tseng M, Murray SC, Kupper LL, et al (1996). Micronutrients and the risk of colorectal adenomas. Am J Epidemiol, 144, 1005-14.
  30. Weisberg I, Tran P, Christensen B, et al (1998). A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab, 64, 169-72.
  31. Wang K, Zhang JT, Yun YX, et al (2011). Improvement on PCR-CTPP: a SNP genotyping approach based on mismatch technique. HEREDITAS, 33, 182-8.
  32. Wang LD, Guo RF, Fan ZM, et al (2005). Association of methylenetetrahydrofolate reductase and thymidylate synthase promoter polymorphisms with genetic susceptibility to esophageal and cardia cancer in a Chinese high-risk population. Dis Esophagus, 18, 177-84.
  33. Wang Y, Guo W, He Y, et al (2007). Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer Causes Control, 18, 143-52.
  34. Weinstein SJ, Gridley G, Harty LC, et al (2002). Folate intake, serum homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T genotype are not associated with oral cancer risk in Puerto Rico. J Nutr, 132, 762-7.
  35. Wu JZ, Gao CM, Ding JH, et al (2002). Polymorphisms of methylenetetrahydrofolate reductase C677T and the risk of esophageal cancer. Tumor, 22, 268-70.
  36. Wu M, Liu AM, Kampman E, et al (2009). Green tea drinking, high tea temperature and esophageal cancer in high- and lowrisk areas of Jiangsu Province, China: A population-based case–control study. Int J Cancer, 124, 1907-13.
  37. Yamada K, Chen Z, Rozen R, et al (2001). Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. P Natl Acad Sci USA, 98, 14853-8.
  38. Yang CX, Matsuo K, Ito H, et al (2005). Gene-environment interactions between alcohol drinking and the MTHFR C677T polymorphism impact on esophageal cancer risk: results of a case-control study in Japan. Carcinogenesis, 26, 1285-90.
  39. Yang L, Parkin DM, Li L, et al (2003). Time trends in cancer mortality in China: 1987–1999. Int J Cancer, 106, 771-83.
  40. Zhang J, Zotz RB, Li Y, et al. (2004). Methylenetetrahydrofolate reductase C677T polymorphism and predisposition towards esophageal squamous cell carcinoma in a German Caucasian and a northern Chinese population. J Cancer Res Clin Oncol, 130, 574-80.

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