Breast Cancer Research and Treatment

, Volume 106, Issue 2, pp 263–271 | Cite as

Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis

  • Debora Macis
  • Patrick Maisonneuve
  • Harriet Johansson
  • Bernardo Bonanni
  • Edoardo Botteri
  • Simona Iodice
  • Barbara Santillo
  • Silvana Penco
  • Giacomo Gucciardo
  • Giuseppe D’Aiuto
  • Marco Rosselli del Turco
  • Marinella Amadori
  • Alberto Costa
  • Andrea Decensi
Epidemiology

Abstract

Background

A reduced activity of methylenetetrahydrofolate reductase (MTHFR) due to frequent C677T polymorphism affects DNA synthesis, repair and methylation and may be implicated in breast cancer risk.

Methods

We conducted a nested case-control study within a phase III prevention trial of tamoxifen. After a median follow-up of 81.2 months, 79 of the 5,408 hysterectomised women aged 35–70 years, who had received either tamoxifen 20 mg/day or placebo for 5 years, developed breast cancer. A total of 46 breast cancer cases and 80 unaffected controls matched to treatment allocation, years from randomization (±2 years) and age at randomization (±5 years), underwent genotyping for MTHFR C677T polymorphism using real time PCR.

Results

The MTHFR 677 genotype frequencies for CC, CT, TT in breast cancer cases were 30%, 44% and 26%, respectively, and 35%, 51%, 14% in controls. We observed a borderline significant odds ratio of 2.51 (95% CI, 0.96–6.55) of breast cancer in subjects with 677TT genotype, with no further association after stratifying for age and treatment group. A meta-analysis of 18 studies, including our own, showed an increased risk of breast cancer in premenopausal women with 677TT genotype, with an odds ratio of 1.42 (95% CI, 1.02–1.98).

Conclusions

Our study lends support to a positive association between the MTHFR variant homozygous allele 677TT and breast cancer risk. Additional studies are warranted to provide further insight into the role of folate metabolism deficiency and breast cancer.

Keywords

Meta-analysis Methylenetetrahydrofolate reductase Nested case-control study 

Notes

Acknowledgements

We acknowledge the support of a FIRC (Fondazione Italiana Ricerca sul Cancro) fellowship to Debora Macis, grants from AICF (American Italian Cancer Foundation), AIRC (Associazione Italiana Ricerca sul Cancro) and LILT (Lega Italiana Lotta Tumori).

References

  1. 1.
    Kim YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10(2):66–88CrossRefPubMedGoogle Scholar
  2. 2.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113CrossRefPubMedGoogle Scholar
  3. 3.
    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(2):195–200CrossRefPubMedGoogle Scholar
  4. 4.
    Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 99(8):5606–5611CrossRefPubMedGoogle Scholar
  5. 5.
    Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, Malinow MR, Willett WC, Rozen R (1996) Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation 94(10):2410–2416PubMedGoogle 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(1):7–9PubMedGoogle Scholar
  7. 7.
    Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE (2001) Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 22(4):195–201CrossRefPubMedGoogle Scholar
  8. 8.
    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
  9. 9.
    Chen J, Giovannucci E, Kelsey K, Rimm EB, Stampfer MJ, Colditz GA, Spiegelman D, Willett WC, Hunter DJ (1996) A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 56(21):4862–4864PubMedGoogle Scholar
  10. 10.
    Shen H, Xu Y, Zheng Y, Qian Y, Yu R, Qin Y, Wang X, Spitz MR, Wei Q (2001) Polymorphisms of 5,10-methylenetetrahydrofolate reductase and risk of gastric cancer in a Chinese population: a case-control study. Int J Cancer 95(5):332–336CrossRefPubMedGoogle Scholar
  11. 11.
    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
  12. 12.
    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
  13. 13.
    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
  14. 14.
    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
  15. 15.
    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(1):65–71CrossRefPubMedGoogle Scholar
  16. 16.
    Campbell IG, Baxter SW, Eccles DM, Choong DY (2002) Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res 4(6):R14. doi: 10.1186/bcr457CrossRefPubMedGoogle Scholar
  17. 17.
    Semenza JC, Delfino RJ, Ziogas A, Anton-Culver H (2003) Breast cancer risk and methylenetetrahydrofolate reductase polymorphism. Breast Cancer Res Treat 77(3):217–223CrossRefPubMedGoogle Scholar
  18. 18.
    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(2):169–172CrossRefPubMedGoogle Scholar
  19. 19.
    Ergul E, Sazci A, Utkan Z, Canturk NZ (2003) Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biol 24(6):286–290CrossRefPubMedGoogle Scholar
  20. 20.
    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(2):190–196CrossRefPubMedGoogle Scholar
  21. 21.
    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(4):917–922PubMedGoogle Scholar
  22. 22.
    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(2):116–121PubMedGoogle Scholar
  23. 23.
    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(5B):3215–3219PubMedGoogle Scholar
  24. 24.
    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(6):3863–3868PubMedGoogle Scholar
  25. 25.
    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(12):2071–2077PubMedGoogle Scholar
  26. 26.
    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(4):1606–1614CrossRefPubMedGoogle Scholar
  27. 27.
    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(1):57–65CrossRefPubMedGoogle Scholar
  28. 28.
    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(1):115–117CrossRefPubMedGoogle Scholar
  29. 29.
    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(5):889–893PubMedGoogle Scholar
  30. 30.
    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(12):3015–3018CrossRefPubMedGoogle Scholar
  31. 31.
    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(11):2295–2300CrossRefPubMedGoogle Scholar
  32. 32.
    Jakubowska A, Gronwald J, Menkiszak J, Gorski B, Huzarski T, Byrski T, Edler L, Lubinski J, Scott RJ, Hamann U (2006) Methylenetetrahydrofolate reductase polymorphisms modify BRCA1-associated breast and ovarian cancer risks. Breast Cancer Res Treat. doi: 10.1007/s10549-006-9417-3Google Scholar
  33. 33.
    Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, Rotmensz N, Boyle P (1998) Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study 352(9122):93–97Google Scholar
  34. 34.
    Veronesi U, Maisonneuve P, Rotmensz N, Costa A, Sacchini V, Travaglini R, D’Aiuto G, Lovison F, Gucciardo G, Muraca MG, Pizzichetta MA, Conforti S, Decensi A, Robertson C, Boyle P (2003) Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst 95(2):160–165PubMedGoogle Scholar
  35. 35.
    Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J (2005) A method for meta-analysis of molecular association studies. Stat Med 24(9):1291–1306CrossRefPubMedGoogle Scholar
  36. 36.
    Greenland S (1987) Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 9:1–30PubMedGoogle Scholar
  37. 37.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188CrossRefPubMedGoogle Scholar
  38. 38.
    Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634PubMedGoogle Scholar
  39. 39.
    Copas JB, Shi JQ (2001) A sensitivity analysis for publication bias in systematic reviews. Stat Methods Med Res 10(4):251–265CrossRefPubMedGoogle Scholar
  40. 40.
    Sellers TA, Kushi LH, Cerhan JR, Vierkant RA, Gapstur SM, Vachon CM, Olson JE, Therneau TM, Folsom AR (2001) Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 12(4):420–428CrossRefPubMedGoogle Scholar
  41. 41.
    Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR, Gao YT, Zheng W (2001) Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res 61(19):7136–7141PubMedGoogle Scholar
  42. 42.
    Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA, Hankinson SE (2003) Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 95(5):373–380PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, Speizer FE, Willett WC (1999) A prospective study of folate intake and the risk of breast cancer. JAMA 281(17):1632–1637CrossRefPubMedGoogle Scholar
  44. 44.
    Rohan TE, Jain MG, Howe GR, Miller AB (2000) Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 92(3):266–269CrossRefPubMedGoogle Scholar
  45. 45.
    Gershoni-Baruch R, Dagan E, Israeli D, Kasinetz L, Kadouri E, Friedman E (2000) Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women. Eur J Cancer 36(18):2313–2316CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Debora Macis
    • 1
  • Patrick Maisonneuve
    • 2
  • Harriet Johansson
    • 1
  • Bernardo Bonanni
    • 1
  • Edoardo Botteri
    • 2
  • Simona Iodice
    • 2
  • Barbara Santillo
    • 2
  • Silvana Penco
    • 3
  • Giacomo Gucciardo
    • 4
  • Giuseppe D’Aiuto
    • 5
  • Marco Rosselli del Turco
    • 6
  • Marinella Amadori
    • 7
  • Alberto Costa
    • 8
  • Andrea Decensi
    • 1
    • 9
  1. 1.Division of ChemopreventionEuropean Institute of OncologyMilanItaly
  2. 2.Division of Epidemiology and BiostatisticsEuropean Institute of OncologyMilanItaly
  3. 3.Niguarda HospitalMilanItaly
  4. 4.Ospedale San Camillo ForlaniniRomeItaly
  5. 5.Istituto per lo Studio e la Cura dei Tumori “Fondazione Pascale”NaplesItaly
  6. 6.Centro per lo Studio e la Prevenzione OncologicaFlorenceItaly
  7. 7.Ospedale G.B. MorganiForliItaly
  8. 8.Fondazione MaugeriPaviaItaly
  9. 9.SC Oncologia Medica e PreventivaE.O. Ospedali GallieraGenoaItaly

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