Skip to main content

Advertisement

Log in

Quantitative assessment of the effect of MTHFR polymorphisms on the risk of lung carcinoma

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Published studies on the relationships between 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and lung cancer risk have been conflicting. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between MTHFR C677T and A1298C polymorphisms and lung cancer risk. A total of 15 studies including 10,753 cases and 11,275 controls described C677T genotypes, among which 11 articles totalling 6,161 cases and 7,684 controls described A1298C genotypes, were also involved in this meta-analysis. Overall, no significantly elevated lung cancer risk was found in any genetic models when all studies were pooled. For C677T polymorphism: (TT vs. CC: OR = 1.17, 95% CI = 0.97–1.42; TC vs. CC: OR = 1.06, 95% CI = 0.94–1.20; dominant model: OR = 1.09, 95% CI = 0.96–1.24; and recessive model: OR = 1.08, 95% CI = 0.95–1.24); for A1298C polymorphism: (CC vs. AA: OR = 1.04, 95% CI = 0.91–1.19; AC vs. AA: OR = 0.98, 95% CI = 0.91–1.06; dominant model: OR = 0.99, 95% CI = 0.92–1.06; and recessive model: OR = 1.05, 95% CI = 0.92–1.20). In the subgroup analyses, the results showed that 677T varients could decrease lung cancer risk in female (OR = 0.63, 95% CI = 0.41–0.95, P-value = 0.03, 677CC as reference). No evidence of any associations of MTHFR A1298C polymorphism with lung cancer was found in overall or subgroup analyses. Our meta-analysis supports that the common polymorphisms of C677T and A1298C in MTHFR gene are not susceptibility gene for lung cancer from currently available evidence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    Article  PubMed  Google Scholar 

  2. Shields PG (2002) Molecular epidemiology of smoking and lung cancer. Oncogene 21:6870–6876

    Article  PubMed  CAS  Google Scholar 

  3. Perera FP (1998) Molecular epidemiology of environmental carcinogenesis. Recent Results Cancer Res 154:39–46

    Article  PubMed  CAS  Google Scholar 

  4. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet 7:551

    Article  PubMed  CAS  Google Scholar 

  5. Weisberg IS, Jacques PF, Selhub J, Bostom AG, Chen Z, Curtis Ellison R, Eckfeldt JH, Rozen R (2001) The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis 156:409–415

    Article  PubMed  CAS  Google Scholar 

  6. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62:1044–1051

    Article  PubMed  Google Scholar 

  7. 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 9:849–853

    PubMed  CAS  Google Scholar 

  8. Mao R, Fan Y, Jin Y, Bai J, Fu S (2008) Methylenetetrahydrofolate reductase gene polymorphisms and lung cancer: a meta-analysis. J Hum Genet 53:340–348

    Article  PubMed  CAS  Google Scholar 

  9. Boccia S, Boffetta P, Brennan P, Ricciardi G, Gianfagna F, Matsuo K, van Duijn CM, Hung RJ (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

    Article  PubMed  CAS  Google Scholar 

  10. Guo SW, Thompson EA (1992) Performing the exact test of Hardy–Weinberg proportion for multiple alleles. Biometrics 48:361–372

    Article  PubMed  CAS  Google Scholar 

  11. Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19:251–253

    Article  PubMed  CAS  Google Scholar 

  12. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  13. Ioannidis JP, Patsopoulos NA, Evangelou E (2007) Uncertainty in heterogeneity estimates in meta-analyses. BMJ 335:914–916

    Article  PubMed  Google Scholar 

  14. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  PubMed  CAS  Google Scholar 

  15. Cui LH, Shin MH, Kim HN, Song HR, Piao JM, Kweon SS, Choi JS, Yun WJ, Kim YC, Oh IJ, Kim KS (2011) Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population. BMC Med Genet 12:28

    Article  PubMed  CAS  Google Scholar 

  16. Arslan S, Karadayi S, Yildirim ME, Ozdemir O, Akkurt I (2010) The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk. Mol Biol Rep 38(2):991–996

    Article  PubMed  Google Scholar 

  17. Liu CS, Tsai CW, Hsia TEC, Wang RF, Liu CJ, Hang LW, Chiang SUY, Wang CH, Tsai RY, Lin CC, Bau DAT (2009) Interaction of methylenetetrahydrofolate reductase genotype and smoking habit in Taiwanese lung cancer patients. Cancer Genomics Proteomics 6:325–329

    PubMed  CAS  Google Scholar 

  18. Liu H, Jin G, Wang H, Wu W, Liu Y, Qian J, Fan W, Ma H, Miao R, Hu Z, Sun W, Wang Y, Jin L, Wei Q, Shen H, Huang W, Lu D (2008) Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case–control study in Chinese population. Lung Cancer 61:21–29

    Article  PubMed  CAS  Google Scholar 

  19. Vineis P, Veglia F, Garte S, Malaveille C, Matullo G, Dunning A, Peluso M, Airoldi L, Overvad K, Raaschou-Nielsen O, Clavel-Chapelon F, Linseisen JP, Kaaks R, Boeing H, Trichopoulou A, Palli D, Crosignani P, Tumino R, Panico S, Bueno-De-Mesquita HB, Peeters PH, Lund E, Gonzalez CA, Martinez C, Dorronsoro M, Barricarte A, Navarro C, Quiros JR, Berglund G, Jarvholm B, Day NE, Key TJ, Saracci R, Riboli E, Autrup H (2007) Genetic susceptibility according to three metabolic pathways in cancers of the lung and bladder and in myeloid leukemias in nonsmokers. Ann Oncol 18:1230–1242

    Article  PubMed  CAS  Google Scholar 

  20. Suzuki T, Matsuo K, Hiraki A, Saito T, Sato S, Yatabe Y, Mitsudomi T, Hida T, Ueda R, Tajima K (2007) Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case–control study. Carcinogenesis 28:1718–1725

    Article  PubMed  CAS  Google Scholar 

  21. Jin C, Zhang YH, Peng MF, Li WD, Ma L, Chen WS (2007) Research of relationship between gene polymorphisms of methylenetetrahydrofolate reductase enzyme and lung cancer. Chin J Cancer Prev Treat 14:888–891

    CAS  Google Scholar 

  22. Hung RJ, Hashibe M, McKay J, Gaborieau V, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates I, Foretova L, Janout V, Bencko V, Chabrier A, Moullan N, Canzian F, Hall J, Boffetta P, Brennan P (2007) Folate-related genes and the risk of tobacco-related cancers in Central Europe. Carcinogenesis 28:1334–1340

    Article  PubMed  CAS  Google Scholar 

  23. Zhang XM, Miao XP, Tan W, Qu SN, Sun T, Zhou YF, Lin DX (2005) Association between genetic polymorphisms in methylentetrahydrofolate reductase and risk of lung cancer. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 27:700–703

    PubMed  CAS  Google Scholar 

  24. Shi Q, Zhang Z, Li G, Pillow PC, Hernandez LM, Spitz MR, Wei Q (2005) Sex differences in risk of lung cancer associated with methylene-tetrahydrofolate reductase polymorphisms. Cancer Epidemiol Biomarkers Prev 14:1477–1484

    Article  PubMed  CAS  Google Scholar 

  25. Shen M, Rothman N, Berndt SI, He X, Yeager M, Welch R, Chanock S, Caporaso N, Lan Q (2005) Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China. Lung Cancer 49:299–309

    Article  PubMed  Google Scholar 

  26. Siemianowicz K, Gminski J, Garczorz W, Slabiak N, Goss M, Machalski M, Magiera-Molendowska H (2003) Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms in patients with small cell and non-small cell lung cancer. Oncol Rep 10:1341–1344

    PubMed  CAS  Google Scholar 

  27. Jeng YL, Wu MH, Huang HB, Lin WY, You SL, Chu TY, Chen CJ, Sun CA (2003) The methylenetetrahydrofolate reductase 677C→T polymorphism and lung cancer risk in a Chinese population. Anticancer Res 23:5149–5152

    PubMed  CAS  Google Scholar 

  28. Heijmans BT, Boer JM, Suchiman HE, Cornelisse CJ, Westendorp RG, Kromhout D, Feskens EJ, Slagboom PE (2003) A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer. Cancer Res 63:1249–1253

    PubMed  CAS  Google Scholar 

  29. Shen H, Spitz MR, Wang LE, Hong WK, Wei Q (2001) Polymorphisms of methylene-tetrahydrofolate reductase and risk of lung cancer: a case–control study. Cancer Epidemiol Biomarkers Prev 10:397–401

    PubMed  CAS  Google Scholar 

  30. Piskac-Collier AL, Monroy C, Lopez MS, Cortes A, Etzel CJ, Greisinger AJ, Spitz MR, El-Zein RA (2011) Variants in folate pathway genes as modulators of genetic instability and lung cancer risk. Genes Chromosomes Cancer 50:1–12

    Article  PubMed  CAS  Google Scholar 

  31. Cui LH, Yu Z, Zhang TT, Shin MH, Kim HN, Choi JS (2011) 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

    Article  PubMed  CAS  Google Scholar 

  32. Jin F, Qu LS, Shen XZ (2009) Association between the methylenetetrahydrofolate reductase C677T polymorphism and hepatocellular carcinoma risk: a meta-analysis. Diagn Pathol 4:39

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We also want to thank Pro. Melissa L. Bondy, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, for providing serviceable advice on our study.

Conflict of interest

None declared.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xiang Ming Cao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Y., Chen, G.Q., Ji, Y. et al. Quantitative assessment of the effect of MTHFR polymorphisms on the risk of lung carcinoma. Mol Biol Rep 39, 6203–6211 (2012). https://doi.org/10.1007/s11033-011-1439-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-011-1439-1

Keywords

Navigation