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, pinteraction = 0.088; C677T, pinteraction = 0.026).


CONCLUSIONS
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.
Martin
Damali N
DN
Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. martinda@mail.nih.gov
Boersma
Brenda J
BJ
Howe
Tiffany M
TM
Goodman
Julie E
JE
Mechanic
Leah E
LE
Chanock
Stephen J
SJ
Ambs
Stefan
S
D000225:Adenine; D001741:Black or African American / Q000235:genetics; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000401:mortality*; D003596:Cytosine; D005260:Female; D005838:Genotype; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D016019:Survival Analysis; D013941:Thymine; D044465:White People / Q000235:genetics
D003596:Cytosine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000225:Adenine; D013941:Thymine