Background: Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism. A common single nucleotide polymorphism (SNP) in MTHFR gene (C677T) results in an aminoacid substitution of alanine into valine, leading to a thermolabile enzyme with reduced activity. Previous studies have shown an association between the omozygote allele MTHFR 677TT and breast cancer. Methods and results: We conducted a nested case-control study in a phase III double-blind placebo-controlled multicentric prevention trial of tamoxifen in 5,408 hysterectomized women aged 35-70 years, who had received either tamoxifen 20 mg/day or placebo for 5 years. After a median follow-up of 81.2 months, 79 subjects were diagnosed with breast cancer. Forty-six patients (cases) consented a blood withdrawal as well as 80 controls without breast cancer, randomly selected and matched for age (+2 years), randomization date (+6 months) and participating center. We genotyped cases and control subjects for MTHFR C677T polymorphism with a real time PCR method. The MTHFR 677 genotype frequencies for CC, CT, TT were 30%, 44% and 26% respectively in breast cancer cases and 35%, 51%, 14% in controls, as shown in table 1. We observed a borderline significant relative risk of 2.51 (95% CI 0.96-6.55, p=0.06) for breast cancer in subjects with 677TT genotype, while no further association was found after stratifying for age and treatment group. Conclusions: This finding suggests a positive association between the MTHFR variant omozygote allele 677TT and breast cancer risk. It is likely that additional environmental conditions, such as dietary folate intake, ethnic factors, different SNPs and genetic mutations, can modulate the overall risk. Further studies are needed to better understand the contribution of this SNP to increased breast cancer risk. Table 1 Debora Macis was supported by a fellowship from FIRC (Fondazione Italiana Ricerca sul Cancro)

[Proc Amer Assoc Cancer Res, Volume 47, 2006]