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



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.


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.


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).


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.


Meta-analysis Methylenetetrahydrofolate reductase Nested case-control study 



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).


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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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