Folate Pathway Gene MTHFR C677T Polymorphism and Risk of Lung Cancer in Asian Populations

  • Rai, Vandana (Department of Biotechnology, Human Molecular Laboratory, VBS Purvanchal University)
  • Published : 2014.11.28


Background: Previous studies concerning the association between the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism with lung cancer in Asian populations have provided inconclusive findings. Aim: A meta-analysis was performed to investigate a more reliable association between MTHFR C677T polymorphism and lung cancer in Asians. Materials and Methods: A comprehensive search was conducted to identify all case-control studies of MTHFR polymorphisms and lung cancer in Asia, using odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of any association. Results: Meta-analysis results suggested that the MTHFR C677T polymorphism contributed to an increased lung cancer risk in Asian populations (for T vs C: OR=1.11, 95%CI=1.0-1.23; for CT vs CC: OR= 1.1, 95%CI= 0.95-1.2 ; for TT+CT vs CC: OR=1.13, 95%CI=1.0-1.30; for TT vs CC: OR=1.25, 95%CI=1.01-1.30; for TT vs CT+CC: OR=1.16, 95%CI=1.0-1.36). Conclusions: MTHFR C677T polymorphism is significantly associated with lung cancer in Asians.


  1. Bailey LB, Gregory JF (1999). Folate metabolism and requirements. J Nutrit, 129, 779-82.
  2. Bax L, Yu LM, Ikeda N, et al (2006). Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med Res Methodol, 6, 50.
  3. Begg CB, Mazumdar M (1994). Operating characteristics of a rank correlation test for publication bias. Biometrics, 50, 1088-101.
  4. 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.
  5. Boccia S, Boffetta P, Brennan P, et al (2009). Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer. Cancer Lett, 273, 55-61.
  6. Botto LD, Yang Q (2000). 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol, 151, 862-77.
  7. Cheng Z, Wang W, Song YN, et al (2011). Investigation of the relationship between C677T polymorphisms of methylenetetra-hydrofolate reductase and lung cancer risk. Chin J Tuberc Respir Dis, 34, 57 58.
  8. Cui LH, Shin MH, Kim HN, et al (2011a). Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population. BMC Med Genet, 12, 28.
  9. Cui LH, Yu Z, Zhang TT, et al (2011b). Influence of polymorphisms in MTHFR 677 C/T, TYMS 3R/2R and MTR 2756 A/G on NSCLC risk and response to platinum-based chemotherapy in advanced NSCLC. Pharmacogenomics, 12, 797-808.
  10. DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Controlled Clinical Trials, 7, 177-88.
  11. Duthie SJ (1999). Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull, 55, 578-92.
  12. Egger M, Davey Smith G, Schneider M, et al (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629-34.
  13. Ferlay J, Shin HR, Bray F, et al (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 127, 2893-917.
  14. Frosst P, Blom HJ, Milos R, et al (1995). A candidate genetic risk factor for vascular disease: a common mutation in methelenetetrahydrofolate reductase. Nat Genet, 10, 111-3
  15. Guan P, Huang D, Yin Z, et al (2011). Association of the hOGG1 Ser326Cys polymorphism with increased lung cancer susceptibility in Asians: a meta-analysis of 18 studies including 7592 cases and 8129 controls. Asian Pac J Cancer Prev, 12, 1067-72.
  16. Goyette P, Sumner JS, Milos R, et al (1994). Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet, 7, 551.
  17. Goyette P, Pai A, Milos R, et al (1998). Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome, 9, 652-6.
  18. Hegele RA, Tully C, Young TK, Connelly PW (1997). V677 mutation of methylenetetrahydrofolate reductases and cardiovascular disease in Canadian Inuit. Lancet, 349, 1221-2.
  19. Hubner RA, Houlston RS (2007). MTHFR C677T and colorectal cancer risk: a meta analysis of 25 populations. Int J Cancer, 120, 1027-35.
  20. Hung RJ, Hashibe M, McKay J, et al (2007). Folate-related genes and the risk of tobacco-related cancers. Carcinogenesis, 28, 1334-40.
  21. Jeng YL, Wu MH, Huang HB, et al (2003). The methylenetetrahydrofolate reductase 677C$\rightarrow$ T polymorphism and lung cancer risk in a Chinese population. Anticancer Res, 23, 5149-52.
  22. Jin C, Zhang YH, Peng MF, et al (2007). Study of the relationship between C677T, A1298C gene polymorphisms of methylenetetrahydrofolate reductase and lung cancer. Chin Clin Oncol, 12, 671-5.
  23. Kim Y I, Pogribny I P, Basnakian AG, et al (1997). Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am J Clin Nutr, 65, 46-52.
  24. Kim YI (1999). Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem, 10, 66-88.
  25. Kiyohara C, Horiuchi T, Takayama K, Nakanishi Y (2011). Methylenetetrahydrofolate reductase polymorphisms and interaction with smoking and alcohol consumption in lung cancer risk: a case control study in a Japanese population. BMC Cancer, 11, 459.
  26. Liang H, Yan Y, Li T, et al (2013). Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk in Chinese population: a meta-analysis of 22 case-control studies. Tumor Biol, DOI 10.1007/s13277-013-1234-9.
  27. Liao SG, Liu L, Zhang YY, et al (2012). SULT1A1 Arg213His polymorphism and lung cancer risk: a meta-analysis. Asian Pac J Cancer Prev, 13, 579-83.
  28. Liu CS, Tsai CW, Hsia TEC (2009). Interaction of methylenetetrahydrofolate reductase genotype and smoking habit in Taiwanese lung cancer patients. Cancer Genomics Proteomic, 6, 325-9.
  29. Liu H, Jin G, Wang H, et al (2008). Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population. Lung Cancer, 61, 21-9.
  30. Liu ZB, Wang LP, Shu J, Jin C, Lou ZX (2013). Methylenetetrahydrofolate reductase 677TT genotype might be associated with an increased lung cancer risk in Asians. Gene, 515, 214-9.
  31. Mantel N, Haenszel W (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22, 719-48.
  32. Mei Q, Zhou D, Gao J, et al (2012). The association between MTHFR 677C>T polymorphism and cervical cancer: evidence from a meta-analysis. BMC Cancer, 12, 467-76.
  33. Pan F, Tian J, Pan Y, et al (2011). Lack of association of the cyclooxygenase 8473 T>C polymorphism with lung cancer: evidence from 9841 subjects. Asian Pac J Cancer Prev, 12, 1941-5.
  34. Parkin DM, Bray F, Ferlay J, Pisani P (2005). Global cancer statistics, 2002. CA Cancer J Clin, 55, 74-108.
  35. Pepe G, Camacho Vanegas O, Giusti B, et al (1998). Heterogeneity in world distribution of the thermolabile C677T mutation in 5,10-methylenetetrahydrofolate reductase. Am J Hum Genet, 63, 917-20.
  36. Rai V, Yadav U, Kumar P, Yadav SK (2010). Methyleletetrahydrofolate reductase polymorphism (C677T) in Muslim population of Eastern Uttar Pradesh, India. IJMS, 64, 219-23.
  37. Rai V, Yadav U, Kumar P (2012). Prevalence of methylenetetrahydrofolate reductase C677T polymorphism in eastern Uttar Pradesh. Indian J Human Genetics, 18, 43-6.
  38. Rai V (2011). Evaluation of methylenetetrahydrofolate reductase gene variant (C677T) as risk factor for bipolar disorder. Cell Mol Biol, 57, 1558-66.
  39. Rai V (2014). Methylenetetrahydrofolate reductase gene A1298C polymorphism and susceptibility to recurrent pregnancy loss: a meta-analysis. Cell Mol Biol, 60, 27-34.
  40. Robien K, Ulrich CM (2003). 5,10- Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemio, 157, 571-82.
  41. Sharp L, Little J (2004). Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol, 159, 423-43.
  42. Shen M, Rothman N, Berndt SI, et al (2005). Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China. Lung Cancer, 49, 299-309.
  43. Stern LL, Mason JB, Selhub J, Choi SW (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.
  44. Suzuki T, Matsuo K, Hiraki A, et al (2007). Impact of onecarbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case-control study. Carcinogenesis, 28, 1718-25.
  45. Tu YL, Wang SB, Tan XL (2012). MTHFR Gene polymorphisms are not involved in pancreatic cancer risk: A meta-analysis. Asian Pac J Cancer Prev, 13, 4627-30.
  46. 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.
  47. Whitehead A (2002). Meta-analysis of controlled clinical trials. Wiley, Chichester, UK.
  48. Yadav U, Kumar P, Rai V (2011). Docking study of MTHFR with FAD by Hex. J Comput Intell Bioinformatics, 4, 171-8.
  49. Yadav U, Kumar P, Yadav SK, Mishra OP, Rai V (2014). Polymorphisms in folate metabolism genes as maternal risk factor for Neural Tube Defects: an updated meta-analysis. Metabolic Brain Disease.
  50. Yang XX, Li FX, Yi JP, et al (2010). Polymorphisms of the methylenetetrahydrofolate reductase C677T and risk of gastric cancer, colon cancer and lung cancer. Guangdong Med J, 31, 2375-8.
  51. Yao QF, Chen X, Xue JR, et al (2010). Relationship of polymorphisms of MTHFR gene hypermethylation of tumor suppressor gene in lung cancer. Cancer Res Prev Treat, 37, 531-4.
  52. Zhang XM, Miao XP, Tan W, et al (2005). Association between genetic polymorphisms in methylentetrahydrofolate reductase and risk of lung cancer. Acta Academiae Medicinae Sinicae, 27, 700-3.
  53. Zintzaras E, Hadjigeorgiou GM (2005). The role of G196A polymorphism in the brain-derived neurotrophic factor gene in the cause of Parkinson's disease: a meta-analysis. J Hum Genet, 50, 560-6.
  54. Zintzaras E, Ioannidis JP (2005). Heterogeneity testing in meta analysis of genome searches. Genet Epidemiol, 28, 123-37.
  55. Zintzaras E (2007). Maternal gene polymorphisms involved in folate metabolism and risk of Down syndrome offspring: a meta-analysis. J Human Genetics, 52, 943-53.

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