title: Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis.
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.
authors.affiliation: Division of Chemoprevention, European Institute of Oncology, Milan, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Macis
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.forename: Harriet
authors.initials: H
authors.lastname: Johansson
authors.forename: Bernardo
authors.initials: B
authors.lastname: Bonanni
authors.forename: Edoardo
authors.initials: E
authors.lastname: Botteri
authors.forename: Simona
authors.initials: S
authors.lastname: Iodice
authors.forename: Barbara
authors.initials: B
authors.lastname: Santillo
authors.forename: Silvana
authors.initials: S
authors.lastname: Penco
authors.forename: Giacomo
authors.initials: G
authors.lastname: Gucciardo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Aiuto
authors.forename: Marco
authors.initials: M
authors.lastname: Rosselli Del Turco
authors.forename: Marinella
authors.initials: M
authors.lastname: Amadori
authors.forename: Alberto
authors.initials: A
authors.lastname: Costa
authors.forename: Andrea
authors.initials: A
authors.lastname: Decensi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D016032:Randomized Controlled Trials as Topic; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D042965:Methylenetetrahydrofolate Reductase (NADPH2)