Breast Cancer Research and Treatment

, Volume 123, Issue 2, pp 549–555 | Cite as

MTHFR C677T polymorphism associated with breast cancer susceptibility: a meta-analysis involving 15,260 cases and 20,411 controls

  • Jian Zhang
  • Li-Xin Qiu
  • Zhong-Hua Wang
  • Xiang-Hua Wu
  • Xiao-Jian Liu
  • Bi-Yun Wang
  • Xi-Chun Hu


Published data on the association between MTHFR C677T polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the MTHFR C677T polymorphism and breast cancer risk. The pooled ORs were performed with co-dominant model (CT vs. CC, TT vs. CC), dominant model (CT + TT vs. CC), and recessive model (TT vs. CC + CT), respectively. A total of 37 studies including 15,260 cases and 20,411 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with TT variant genotype in homozygote comparison and dominant genetic model when all studies were pooled into the meta-analysis (TT vs. CC: OR = 1.11, 95% CI = 1.01–1.23; dominant model: OR = 1.04, 95% CI = 1.00–1.09). In the subgroup analysis by ethnicity, significantly increased risks were found for TT allele carriers among Asians (TT vs. CC: OR = 1.18, 95% CI = 1.04–1.35; recessive model: OR = 1.15, 95% CI = 1.03–1.29). When stratified by study design, statistically significantly elevated risk was found in hospital-based studies (TT vs. CC: OR = 1.18, 95% CI = 1.02–1.38; recessive model: OR = 1.17, 95% CI = 1.05–1.29). In the subgroup analysis by menopausal status, statistically significantly increased risk was found among postmenopausal women (CT vs. CC: OR = 1.12, 95% CI = 1.02–1.23; dominant model: OR = 1.11, 95% CI = 1.01–1.22). In conclusion, this meta-analysis suggests that the MTHFR T allele is a low-penetrant risk factor for developing breast cancer.


MTHFR Polymorphism Breast cancer Susceptibility Meta-analysis 


  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249CrossRefPubMedGoogle Scholar
  2. 2.
    Dumitrescu RG, Cotarla I (2005) Understanding breast cancer risk—where do we stand in 2005? J Cell Mol Med 9:208–221CrossRefPubMedGoogle Scholar
  3. 3.
    Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85CrossRefPubMedGoogle Scholar
  4. 4.
    Bailey LB, Gregory JR (1999) Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr 129:919–922PubMedGoogle Scholar
  5. 5.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, Et A (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113CrossRefPubMedGoogle Scholar
  6. 6.
    Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93:7–9PubMedGoogle Scholar
  7. 7.
    Kalyankumar Ch, Jamil K (2006) Methylene tetrahydofolate reductase (MTHFR) C677T and A1298C polymorphisms and breast cancer in South Indian population. Int J Cancer Res 2:143–151CrossRefGoogle Scholar
  8. 8.
    Cam R, Eroglu A, Egin Y, Akar N (2009) Dihydrofolate reductase (DHRF) 19-bp intron-1 deletion and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms in breast cancer. Breast Cancer Res Treat 115:431–432CrossRefPubMedGoogle Scholar
  9. 9.
    Campbell IG, Baxter SW, Eccles DM, Choong DY (2002) Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res 4:R14CrossRefPubMedGoogle Scholar
  10. 10.
    Chen J, Gammon MD, Chan W, Palomeque C, Wetmur JG, Kabat GC, Teitelbaum SL, Britton JA, Terry MB, Neugut AI, Santella RM (2005) One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Res 65:1606–1614CrossRefPubMedGoogle Scholar
  11. 11.
    Cheng CW, Yu JC, Huang CS, Shieh JC, Fu YP, Wang HW, Wu PE, Shen CY (2008) Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan. Breast Cancer Res Treat 111:145–155CrossRefPubMedGoogle Scholar
  12. 12.
    Chou YC, Wu MH, Yu JC, Lee MS, Yang T, Shih HL, Wu TY, Sun CA (2006) Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan. Carcinogenesis 27:2295–2300CrossRefPubMedGoogle Scholar
  13. 13.
    Deligezer U, Akisik EE, Dalay N (2005) Homozygosity at the C677T of the MTHFR gene is associated with increased breast cancer risk in the Turkish population. In Vivo 19:889–893PubMedGoogle Scholar
  14. 14.
    Ergul E, Sazci A, Utkan Z, Canturk NZ (2003) Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biol 24:286–290CrossRefPubMedGoogle Scholar
  15. 15.
    Ericson U, Sonestedt E, Ivarsson MI, Gullberg B, Carlson J, Olsson H, Wirfalt E (2009) Folate intake, methylenetetrahydrofolate reductase polymorphisms, and breast cancer risk in women from the Malmo Diet and Cancer cohort. Cancer Epidemiol Biomarkers Prev 18:1101–1110CrossRefPubMedGoogle Scholar
  16. 16.
    Ericson UC, Ivarsson MI, Sonestedt E, Gullberg B, Carlson J, Olsson H, Wirfalt E (2009) Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele. Am J Clin Nutr 90:1380–1389CrossRefPubMedGoogle Scholar
  17. 17.
    Forsti A, Angelini S, Festa F, Sanyal S, Zhang Z, Grzybowska E, Pamula J, Pekala W, Zientek H, Hemminki K, Kumar R (2004) Single nucleotide polymorphisms in breast cancer. Oncol Rep 11:917–922PubMedGoogle Scholar
  18. 18.
    Gao CM, Tang JH, Cao HX, Ding JH, Wu JZ, Wang J, Liu YT, Li SP, Su P, Matsuo K, Takezaki T, Tajima K (2009) MTHFR polymorphisms, dietary folate intake and breast cancer risk in Chinese women. J Hum Genet 54:414–418CrossRefPubMedGoogle Scholar
  19. 19.
    Grieu F, Powell B, Beilby J, Iacopetta B (2004) Methylenetetrahydrofolate reductase and thymidylate synthase polymorphisms are not associated with breast cancer risk or phenotype. Anticancer Res 24:3215–3219PubMedGoogle Scholar
  20. 20.
    Hekim N, Ergen A, Yaylim I, Yilmaz H, Zeybek U, Ozturk O, Isbir T (2007) No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer. Cell Biochem Funct 25:115–117CrossRefPubMedGoogle Scholar
  21. 21.
    Henriquez-Hernandez LA, Murias-Rosales A, Hernandez GA, Cabrera DLA, Diaz-Chico BN, Mori DSM, Fernandez PL (2009) Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: a case-control study. Oncol Rep 22:1425–1433CrossRefPubMedGoogle Scholar
  22. 22.
    Inoue M, Robien K, Wang R, Van Den Berg DJ, Koh WP, Yu MC (2008) Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study. Carcinogenesis 29:1967–1972CrossRefPubMedGoogle Scholar
  23. 23.
    Justenhoven C, Hamann U, Pierl CB, Rabstein S, Pesch B, Harth V, Baisch C, Vollmert C, Illig T, Bruning T, Ko Y, Brauch H (2005) One-carbon metabolism and breast cancer risk: no association of MTHFR, MTR, and TYMS polymorphisms in the GENICA study from Germany. Cancer Epidemiol Biomarkers Prev 14:3015–3018CrossRefPubMedGoogle Scholar
  24. 24.
    Kalemi TG, Lambropoulos AF, Gueorguiev M, Chrisafi S, Papazisis KT, Kotsis A (2005) The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece. Cancer Lett 222:57–65CrossRefPubMedGoogle Scholar
  25. 25.
    Kotsopoulos J, Zhang WW, Zhang S, McCready D, Trudeau M, Zhang P, Sun P, Narod SA (2008) Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Res Treat 112:585–593CrossRefPubMedGoogle Scholar
  26. 26.
    Langsenlehner U, Krippl P, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Weitzer W, Samonigg H (2003) The common 677C > T gene polymorphism of methylenetetrahydrofolate reductase gene is not associated with breast cancer risk. Breast Cancer Res Treat 81:169–172CrossRefPubMedGoogle Scholar
  27. 27.
    Le Marchand L, Haiman CA, Wilkens LR, Kolonel LN, Henderson BE (2004) MTHFR polymorphisms, diet, HRT, and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 13:2071–2077PubMedGoogle Scholar
  28. 28.
    Lee SA, Kang D, Nishio H, Lee MJ, Kim DH, Han W, Yoo KY, Ahn SH, Choe KJ, Hirvonen A, Noh DY (2004) Methylenetetrahydrofolate reductase polymorphism, diet, and breast cancer in Korean women. Exp Mol Med 36:116–121PubMedGoogle Scholar
  29. 29.
    Lin WY, Chou YC, Wu MH, Huang HB, Jeng YL, Wu CC, Yu CP, Yu JC, You SL, Chu TY, Chen CJ, Sun CA (2004) The MTHFR C677T polymorphism, estrogen exposure and breast cancer risk: a nested case-control study in Taiwan. Anticancer Res 24:3863–3868PubMedGoogle Scholar
  30. 30.
    Lissowska J, Gaudet MM, Brinton LA, Chanock SJ, Peplonska B, Welch R, Zatonski W, Szeszenia-Dabrowska N, Park S, Sherman M, Garcia-Closas M (2007) Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses. Int J Cancer 120:2696–2703CrossRefPubMedGoogle Scholar
  31. 31.
    Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, Motola JJ, Laginha FM, Tsugane S (2009) Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women. BMC Cancer 9:122CrossRefPubMedGoogle Scholar
  32. 32.
    Ma E, Iwasaki M, Kobayashi M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S (2009) Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan. Nutr Cancer 61:447–456CrossRefPubMedGoogle Scholar
  33. 33.
    Macis D, Maisonneuve P, Johansson H, Bonanni B, Botteri E, Iodice S, Santillo B, Penco S, Gucciardo G, D’Aiuto G, Rosselli DTM, Amadori M, Costa A, Decensi A (2007) Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis. Breast Cancer Res Treat 106:263–271CrossRefPubMedGoogle Scholar
  34. 34.
    Maruti SS, Ulrich CM, Jupe ER, White E (2009) MTHFR C677T and postmenopausal breast cancer risk by intakes of one-carbon metabolism nutrients: a nested case-control study. Breast Cancer Res 11:R91CrossRefPubMedGoogle Scholar
  35. 35.
    Platek ME, Shields PG, Marian C, McCann SE, Bonner MR, Nie J, Ambrosone CB, Millen AE, Ochs-Balcom HM, Quick SK, Trevisan M, Russell M, Nochajski TH, Edge SB, Freudenheim JL (2009) Alcohol consumption and genetic variation in methylenetetrahydrofolate reductase and 5-methyltetrahydrofolate-homocysteine methyltransferase in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev 18:2453–2459CrossRefPubMedGoogle Scholar
  36. 36.
    Qi J, Miao XP, Tan W, Yu CY, Liang G, Lu WF, Lin DX (2004) Association between genetic polymorphisms in methylenetetrahydrofolate reductase and risk of breast cancer. Zhonghua Zhong Liu Za Zhi 26:287–289PubMedGoogle Scholar
  37. 37.
    Reljic A, Simundic AM, Topic E, Nikolac N, Justinic D, Stefanovic M (2007) The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cancer risk: the Croatian case-control study. Clin Biochem 40:981–985CrossRefPubMedGoogle Scholar
  38. 38.
    Semenza JC, Delfino RJ, Ziogas A, Anton-Culver H (2003) Breast cancer risk and methylenetetrahydrofolate reductase polymorphism. Breast Cancer Res Treat 77:217–223CrossRefPubMedGoogle Scholar
  39. 39.
    Sharp L, Little J, Schofield AC, Pavlidou E, Cotton SC, Miedzybrodzka Z, Baird JO, Haites NE, Heys SD, Grubb DA (2002) Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett 181:65–71CrossRefPubMedGoogle Scholar
  40. 40.
    Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hebert JR, Jin F, Zheng W (2004) MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev 13:190–196CrossRefPubMedGoogle Scholar
  41. 41.
    Sohn KJ, Croxford R, Yates Z, Lucock M, Kim YI (2004) Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst 96:134–144CrossRefPubMedGoogle Scholar
  42. 42.
    Stevens VL, McCullough ML, Pavluck AL, Talbot JT, Feigelson HS, Thun MJ, Calle EE (2007) Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence. Cancer Epidemiol Biomarkers Prev 16:1140–1147CrossRefPubMedGoogle Scholar
  43. 43.
    Suzuki T, Matsuo K, Hirose K, Hiraki A, Kawase T, Watanabe M, Yamashita T, Iwata H, Tajima K (2008) One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis 29:356–362CrossRefPubMedGoogle Scholar
  44. 44.
    Tao MH, Shields PG, Nie J, Marian C, Ambrosone CB, McCann SE, Platek M, Krishnan SS, Xie B, Edge SB, Winston J, Vito D, Trevisan M, Freudenheim JL (2009) DNA promoter methylation in breast tumors: no association with genetic polymorphisms in MTHFR and MTR. Cancer Epidemiol Biomarkers Prev 18:998–1002CrossRefPubMedGoogle Scholar
  45. 45.
    Xu X, Gammon MD, Zhang H, Wetmur JG, Rao M, Teitelbaum SL, Britton JA, Neugut AI, Santella RM, Chen J (2007) Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study. Carcinogenesis 28:1504–1509CrossRefPubMedGoogle Scholar
  46. 46.
    Yu CP, Wu MH, Chou YC, Yang T, You SL, Chen CJ, Sun CA (2007) Breast cancer risk associated with multigenotypic polymorphisms in folate-metabolizing genes: a nested case-control study in Taiwan. Anticancer Res 27:1727–1732PubMedGoogle Scholar
  47. 47.
    Cochran WG (1954) The combination of estimates from different experiments. Biometrics 10:101–129CrossRefGoogle Scholar
  48. 48.
    Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748PubMedGoogle Scholar
  49. 49.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRefPubMedGoogle Scholar
  50. 50.
    Tobias A (1999) Assessing the influence of a single study in the meta-analysis estimate. Stata Tech Bull 8:15–17Google Scholar
  51. 51.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedGoogle Scholar
  52. 52.
    Kundu TK, Rao MR (1999) CpG islands in chromatin organization and gene expression. J Biochem 125:217–222PubMedGoogle Scholar
  53. 53.
    Lengauer C, Kinzler KW, Vogelstein B (1997) DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sci USA 94:2545–2550CrossRefPubMedGoogle Scholar
  54. 54.
    Cheng P, Schmutte C, Cofer KF, Felix JC, Yu MC, Dubeau L (1997) Alterations in DNA methylation are early, but not initial, events in ovarian tumorigenesis. Br J Cancer 75:396–402PubMedGoogle Scholar
  55. 55.
    Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, Willett WC, Selhub J, Hennekens CH, Rozen R (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 57(6):1098–1102PubMedGoogle Scholar
  56. 56.
    Graziano F, Kawakami K, Ruzzo A, Watanabe G, Santini D, Pizzagalli F, Bisonni R, Mari D, Floriani I, Catalano V, Silva R, Tonini G, Torri V, Giustini L, Magnani M (2006) Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk Italian population. Int J Cancer 118(3):628–632CrossRefPubMedGoogle Scholar
  57. 57.
    Esteller M, Garcia A, Martinez-Palones JM, Xercavins J, Reventos J (1997) Germ line polymorphisms in cytochrome-P450 1A1 (C4887 CYP1A1) and methylenetetrahydrofolate reductase (MTHFR) genes and endometrial cancer susceptibility. Carcinogenesis 18(12):2307–2311CrossRefPubMedGoogle Scholar
  58. 58.
    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(5):1341–1344PubMedGoogle Scholar
  59. 59.
    Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 96(22):12810–12815CrossRefPubMedGoogle Scholar
  60. 60.
    Hirschhorn JN, Lohmueller K, Byrne E (2002) A comprehensive review of genetic association studies. Genet Med 4:45–61CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Jian Zhang
    • 1
    • 2
  • Li-Xin Qiu
    • 1
    • 2
  • Zhong-Hua Wang
    • 1
    • 2
  • Xiang-Hua Wu
    • 1
    • 2
  • Xiao-Jian Liu
    • 1
    • 2
  • Bi-Yun Wang
    • 1
    • 2
  • Xi-Chun Hu
    • 1
    • 2
  1. 1.Department of Medical Oncology, Cancer HospitalFudan UniversityShanghaiChina
  2. 2.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina

Personalised recommendations