Association of MTHFR gene polymorphisms with breast cancer survival

Background: Two functional single nucleotide polymorphisms ( SNPs) in the 5,10-methylenetetrahydrofolate reductase ( MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African- American and Caucasian women. Methods: African- American ( n = 143) and Caucasian ( n = 105) women, who had incident breast cancer with surgery, were recruited between 1993 and 2003 from the greater Baltimore area, Maryland, USA. Kaplan- Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between MTHFR SNPs and disease- specific survival. Results: We observed opposite effects of the MTHFR polymorphisms A1298C and C677T on breast cancer survival. Carriers of the variant allele at codon 1298 ( A/ C or C/ C) had reduced survival when compared to homozygous carriers of the common A allele [ Hazard ratio ( HR) = 2.05; 95% confidence interval ( CI), 1.05 - 4.00]. In contrast, breast cancer patients with the variant allele at codon 677 ( C/ T or T/ T) had improved survival, albeit not statistically significant, when compared to individuals with the common C/ C genotype ( HR = 0.65; 95% CI, 0.31 - 1.35). The effects were stronger in patients with estrogen receptor- negative tumors ( HR = 2.70; 95% CI, 1.17 - 6.23 for A/ C or C/ C versus A/ A at codon 1298; HR = 0.36; 95% CI, 0.12 - 1.04 for C/ T or T/ T versus C/ C at codon 677). Interactions between the two MTHFR genotypes and race/ ethnicity on breast cancer survival were also observed ( A1298C, p(interaction) = 0.088; C677T, p(interaction) = 0.026). Conclusion: We found that the MTHFR SNPs, C677T and A1298C, were associated with breast cancer survival. The variant alleles had opposite effects on disease outcome in the study population. Race/ ethnicity modified the association between the two SNPs and breast cancer survival.