Tumor Biology

, Volume 36, Issue 11, pp 8953–8972 | Cite as

Association between the MTHFR C677T polymorphism and risk of cancer: evidence from 446 case–control studies

  • Shu-Zhe Xie
  • Zhi-Zhong Liu
  • Jun-hua Yu
  • Li Liu
  • Wei Wang
  • Dao-Lin Xie
  • Jiang-Bo Qin
Research Article


Many molecular epidemiological studies have been performed to explore the association between MTHFR C677T polymorphism and cancer risk in diverse populations. However, the results were inconsistent. Hence, we performed a meta-analysis to investigate the association between cancer risk and MTHFR C677T (150,086 cases and 200,699 controls from 446 studies) polymorphism. Overall, significantly increased cancer risk was found when all eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significantly increased breast cancer risk was found in Asians and Indians, significantly decreased colon cancer risk was found, significantly decreased colorectal cancer risk was found in male population, significantly increased gastric cancer risk was found in Caucasians and Asians, significantly increased hepatocellular cancer risk was found in Asians, significantly decreased adult acute lymphoblastic leukemia (AALL) risk was found in Caucasians, significantly decreased childhood acute lymphoblastic leukemia (CALL) risk was found in Asians, and significantly increased multiple myeloma and NHL risk was found in Caucasians. In summary, this meta-analysis suggests that MTHFR C677T polymorphism is associated with increased breast cancer, gastric cancer, and hepatocellular cancer risk in Asians, is associated with increased gastric cancer, multiple myeloma, and NHL risk in Caucasians, is associated with decreased AALL risk in Caucasians, is associated with decreased CALL risk in Asians, is associated with increased breast cancer risk in Asians, is associated with decreased colon cancer risk, and is associated with decreased colorectal cancer risk in male population. Moreover, this meta-analysis also points out the importance of new studies, such as Asians of HNC, Asians of lung cancer, and Indians of breast cancer, because they had high heterogeneity in this meta-analysis (I 2 > 75 %).


MTHFR Polymorphism Cancer Meta-analysis 


Conflicts of interest


Supplementary material

13277_2015_3648_MOESM1_ESM.doc (720 kb)
Supplementary Table 1 (DOC 719 kb)
13277_2015_3648_MOESM2_ESM.doc (325 kb)
ESM 1 (DOC 325 kb)


  1. 1.
    Kwasniewska A, Tukendorf A, Semczuk M. Folate deficiency and cervical intraepithelial neoplasia. Eur J Gynaecol Oncol. 1997;18:526–30.PubMedGoogle Scholar
  2. 2.
    Eichholzer M, Luthy J, Moser U, Fowler B. Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence. Swiss Med Wkly. 2001;131:539–49.PubMedGoogle Scholar
  3. 3.
    Fodinger M, Horl WH, Sunder-Plassmann G. Molecularbiology of 5,10-methylenetetrahydrofolate reductase. J Nephrol. 2000;13:20–33.PubMedGoogle Scholar
  4. 4.
    Lucock M. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab. 2000;71:121–38.CrossRefPubMedGoogle Scholar
  5. 5.
    Lucock M. Is folic acid the ultimate functional food component for disease prevention? BMJ. 2004;328:211–4.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cicek MS, Nock NL, Li L, Conti DV, Casey G, Witte JS. Relationship between methylenetetrahydrofolate reductase C677T and A1298C genotypes and haplotypes and prostate cancer risk and aggressiveness. Cancer Epidemiol Biomarkers Prev. 2004;13:1331–6.PubMedGoogle Scholar
  7. 7.
    García-Closas R, García-Closas M, Kogevinas M, Malats N, Silverman D, Serra C, et al. Food, nutrient and heterocyclic amine intake and the risk of bladder cancer. Eur J Cancer. 2007;43:1731–40.CrossRefPubMedGoogle Scholar
  8. 8.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111–3.CrossRefPubMedGoogle Scholar
  9. 9.
    Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Friso S, Choi SW. Gene-nutrient interactions in one-carbon metabolism. Curr Drug Metab. 2005;6:37–46.CrossRefPubMedGoogle Scholar
  11. 11.
    Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost. 1997;78:523–6.PubMedGoogle Scholar
  12. 12.
    Niu YM, Deng MH, Chen W, Zeng XT, Luo J. MTHFR C677T gene polymorphism and head and neck cancer risk: a meta-analysis based on 23 publications. Dis Markers. 2015;2015:681313.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Macis D, Maisonneuve P, Johansson H, Bonanni B, Botteri E, Iodice S, et al. Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case–control study and a pooled meta-analysis. Breast Cancer Res Treat. 2007;106:263–71.CrossRefPubMedGoogle Scholar
  14. 14.
    Li K, Li W, Dong X. Association of 677 C>T (rs1801133) and 1298 A>C (rs1801131) polymorphisms in the MTHFR gene and breast cancer susceptibility: a meta-analysis based on 57 individual studies. PLoS One. 2014;9, e71290.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Liu YX, Wang B, Wan MH, Tang WF, Huang FK, Li C. Meta-analysis of the relationship between the metholenetetrahydrofolate reductase C677T genetic polymorphism, folate intake and esophageal cancer. Asian Pac J Cancer Prev. 2011;12:247–52.PubMedGoogle Scholar
  16. 16.
    Fang Y, Xiao F, An Z, Hao L. Systematic review on the relationship between genetic polymorphisms of methylenetetrahydrofolate reductase and esophageal squamous cell carcinoma. Asian Pac J Cancer Prev. 2011;12:1861–6.PubMedGoogle Scholar
  17. 17.
    Xia LZ, Liu Y, Xu XZ, Jiang PC, Ma G, Bu XF, et al. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility. World J Gastroenterol. 2014;20:11429–38.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ramsey SD, Holmes RS, McDermott CL, Blough DK, Petrin KL, Poole EM, et al. A comparison of approaches for association studies of polymorphisms and colorectal cancer risk. Colorectal Dis. 2012;14:e573–86.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hubner RA, Houlston RS. MTHFR C677T and colorectal cancer risk: a meta-analysis of 25 populations. Int J Cancer. 2007;120:1027–35.CrossRefPubMedGoogle Scholar
  20. 20.
    Wang X, Yue K, Hao L. Meta-analysis of methylenetetrahydrofolate reductase polymorphism and lung cancer risk in Chinese. Int J Clin Exp Med. 2015;8:1521–5.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Tang M, Wang SQ, Liu BJ, Cao Q, Li BJ, Li PC, et al. The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and tumor risk: evidence from 134 case–control studies. Mol Biol Rep. 2014;41:4659–73.CrossRefPubMedGoogle Scholar
  22. 22.
    Little J, Bradley L, Bray MS, Clyne M, Dorman J, Ellsworth DL, et al. Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations. Am J Epidemiol. 2002;156:300–10.CrossRefPubMedGoogle Scholar
  23. 23.
    Davey SG, Egger M. Meta-analyses of randomized controlled trials. Lancet. 1997;350:1182.Google Scholar
  24. 24.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. Br Med J. 2003;327:557–60.CrossRefGoogle Scholar
  25. 25.
    Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Natl Cancer Inst. 1959;22:719–48.Google Scholar
  26. 26.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.CrossRefPubMedGoogle Scholar
  27. 27.
    Klug SJ, Ressing M, Koenig J, Abba MC, Agorastos T, Brenna SM, et al. TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies. Lancet Oncol. 2009;10:772–84.CrossRefPubMedGoogle Scholar
  28. 28.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.CrossRefPubMedGoogle Scholar
  29. 29.
    Egger M, Smith DG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Br Med J. 1997;315:629–34.CrossRefGoogle Scholar
  30. 30.
    Friedman G, Goldschmidt N, Friedlander Y, Ben-Yehuda A, Selhub J, Babaey S, et al. A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr. 1999;129:1656–61.PubMedGoogle Scholar
  31. 31.
    Parle-McDermott A, Mills JL, Molloy AM, Carroll N, Kirke PN, Cox C, et al. The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels. Mol Genet Metab. 2006;88:290–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Duthie SJ. Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull. 1999;55:578–92.CrossRefPubMedGoogle Scholar
  33. 33.
    Ames BN. DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res. 2001;475:7–20.CrossRefPubMedGoogle Scholar
  34. 34.
    Hirschhorn JN, Lohmueller K, Byrne E. A comprehensive review of genetic association studies. Genet Med. 2002;4:45–61.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Shu-Zhe Xie
    • 1
  • Zhi-Zhong Liu
    • 2
  • Jun-hua Yu
    • 3
  • Li Liu
    • 4
  • Wei Wang
    • 2
  • Dao-Lin Xie
    • 5
  • Jiang-Bo Qin
    • 6
  1. 1.Department of General SurgeryPeace Hospital of Changzhi Medical CollegeChangzhiChina
  2. 2.Department of GastroenterologyThe Second People’s Hospital of ZhuhaiZhuhaiChina
  3. 3.Department of NeurosurgeryEzhou Central Hospital of Hubei ProvinceEzhouChina
  4. 4.Department of Reproductive MedicineFirst Center HospitalTianjinChina
  5. 5.Department of Ultrasound DiagnosisPeace Hospital of Changzhi Medical CollegeChangzhiChina
  6. 6.Department of Ear, Nose, and ThroatPeace Hospital of Changzhi Medical CollegeChangzhiChina

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