No Association Between MTHFR A1298C Gene Polymorphism and Head and Neck Cancer Risk: A Meta-analysis Based on 9,952 Subjects

  • Niu, Yu-Ming (Department of Stomatology, Taihe Hospital, Hubei University of Medicine) ;
  • Shen, Ming (Institute of Stomatology, Nanjing Medical University) ;
  • Li, Hui (Department of Stomatology, the First Hospital of Huainan) ;
  • Ni, Xiao-Bing (Department of Stomatology, Taihe Hospital, Hubei University of Medicine) ;
  • Zhou, Juan (Department of Stomatology, Taihe Hospital, Hubei University of Medicine) ;
  • Zeng, Xian-Tao (Department of Stomatology, Taihe Hospital, Hubei University of Medicine) ;
  • Leng, Wei-Dong (Department of Stomatology, Taihe Hospital, Hubei University of Medicine) ;
  • Wu, Ming-Yue (School of Stomatology, Anhui Medical University)
  • Published : 2012.08.31


Objective: Findings for associations between the methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and head and neck cancer risk have been conflicting. We therefore performed a meta-analysis to derive a more precise relationship. Methods: Ten published case-control studies were collected and odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between MTHFR A1298C polymorphism and head and neck cancer risk. Sensitivity analysis and publication bias assessment also were performed to guarantee the statistical power. Results: Overall, no significant association between MTHFR A1298C polymorphism and head and neck cancer risk was found in this meta-analysis (C vs. A: OR=1.04, 95%CI=0.87-1.25, P=0.668, Pheterogeneity<0.001; CC vs. AA: OR=1.07, 95%CI=0.70-1.65, P=0.748, $P_{heterogeneity}<0.001$; AC vs. AA: OR=1.06, 95%CI=0.88-1.27, P=0.565, $P_{heterogeneity}<0.001$; CC+AC vs. AA: OR=1.06, 95%CI=0.86-1.30, P=0.571, $P_{heterogeneity}<0.001$; CC vs. AA+AC: OR=1.02, 95%CI=0.69-1.52, P=0.910, $P_{heterogeneity}<0.001$). Similar results were also been found in succeeding analysis of HWE and stratified analysis of ethnicity. Conclusion: In conclusion, our meta-analysis demonstrates that MTHFR A1298C polymorphism may not be a risk factor for developing head and neck cancer.


  1. Argiris A, Karamouzis MV, Raben D, et al (2008). Head and neck cancer. Lancet, 371, 1695-709.
  2. Blount BC, Mack MM, Wehr CM, et al (1997). Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA, 94, 3290-5.
  3. Cao Y, Miao XP, Huang MY, et al (2010). Polymorphisms of methylenetetrahydrofolate reductase are associated with a high risk of nasopharyngeal carcinoma in a smoking population from Southern China. Mol Carcinog, 49, 928-34.
  4. Capaccio P, Ottaviani F, Cuccarini V, et al (2005). Association between methylenetetrahydrofolate reductase polymorphisms, alcohol intake and oropharyngolaryngeal carcinoma in northern Italy. J Laryngol Otol, 119, 371-6.
  5. DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177-88.
  6. Galbiatti AL, Ruiz MT, Rodrigues JO, et al (2012). Polymorphisms and haplotypes in methylenetetrahydrofolate reductase gene and head and neck squamous cell carcinoma risk. Mol Biol Rep, 39, 635-43.
  7. Harbord RM, Egger M, Sterne JA (2006). A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med, 25, 3443-57.
  8. Hung RJ, Hashibe M, McKay J, et al (2007). Folate-related genes and the risk of tobacco-related cancers in Central Europe. Carcinogenesis, 28, 1334-40.
  9. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  10. Kawakami K, Ruszkiewicz A, Bennett G, et al (2003). The folate pool in colorectal cancers is associated with DNA hypermethylation and with a polymorphism in methylenetetrahydrofolate reductase. Clin Cancer Res, 9, 5860-5.
  11. Kim YI (1999). Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem, 10, 66-88.
  12. Kim YI (1999). Folate and cancer prevention: a new medical application of folate beyond hyperhomocysteinemia and neural tube defects. Nutr Rev, 57, 314-21.
  13. Kruszyna L, Lianeri M, Rydzanicz M, et al (2010). Polymorphic variants of folate metabolism genes and the risk of laryngeal cancer. Mol Biol Rep, 37, 241-7.
  14. Lau J, Ioannidis JP, Schmid CH (1997). Quantitative synthesis in systematic reviews. Ann Intern Med, 127, 820-6.
  15. Lievers KJ, Boers GH, Verhoef P, et al (2001). A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J Mol Med (Berl), 79, 522-8.
  16. Little J, Bradley L, Bray MS, et al (2002). Reporting, appraising, and integrating data on genotype prevalence and genedisease associations. Am J Epidemiol, 156, 300-10.
  17. Mantel N, Haenszel W (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22, 719-48.
  18. Neumann AS, Lyons HJ, Shen H, et al (2005). Methylenetetrahydrofolate reductase polymorphisms and risk of squamous cell carcinoma of the head and neck: a case-control analysis. Int J Cancer, 115, 131-6.
  19. Ni X, Tai J, Ma LJ, et al (2008). [Association between genetic polymorphisms in methylenetetrahydrofolate reductase and risk of laryngeal squamous cell carcinoma]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, 43, 435-8.
  20. Parle-McDermott A, Mills JL, Molloy AM, et al (2006). The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels. Mol Genet Metab, 88, 290-4.
  21. Ragin CC, Modugno F, Gollin SM (2007). The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J Dent Res, 86, 104-14.
  22. Sailasree R, Nalinakumari KR, Sebastian P, et al (2011). Influence of methylenetetrahydrofolate reductase polymorphisms in oral cancer patients. J Oral Pathol Med, 40, 61-6.
  23. 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.
  24. Suzuki T, Matsuo K, Hasegawa Y, et al (2007). One-carbon metabolism-related gene polymorphisms and risk of head and neck squamous cell carcinoma: case-control study. Cancer Sci, 98, 1439-46.
  25. Tsai CW, Hsu CF, Tsai MH, et al (2011). Methylenetetrahydrofolate reductase (MTHFR) genotype, smoking habit, metastasis and oral cancer in Taiwan. Anticancer Res, 31, 2395-9.
  26. van der Put NM, Gabreels F, Stevens EM, et al (1998). A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet, 62, 1044-51.
  27. 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.
  28. Weisberg IS, Jacques PF, Selhub J, et al (2001). The 1298A-- >C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis, 156, 409-15.

Cited by

  1. Association between the TP53 codon 72 polymorphism and risk of oral squamous cell carcinoma in Asians: a meta-analysis vol.14, pp.1, 2014,
  2. Association of Cyclin D1 Variants with Head and Neck Cancer Susceptibility: Evidence from a Meta-analysis vol.15, pp.14, 2014,
  3. Association between MTHFR Polymorphisms and Acute Myeloid Leukemia Risk: A Meta-Analysis vol.9, pp.2, 2014,
  4. Evaluation of the MTHFR C677T Polymorphism as a Risk Factor for Colorectal Cancer in Asian Populations vol.16, pp.18, 2016,
  5. Meta-Analysis Results on the Association Between TP53 Codon 72 Polymorphism With the Susceptibility to Oral Cancer vol.9, pp.1664-042X, 2018,