Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses

Int J Cancer. 2007 Jun 15;120(12):2696-703. doi: 10.1002/ijc.22604.


Epidemiological evidence suggests that intake of folate and other B-vitamins and genetic variants in the one-carbon metabolism pathway could influence the risk of breast cancer. Previous studies have focused on 2 polymorphisms in the methylenetetrahydrofolate gene (MTHFR A222V and E429A); however, findings are inconclusive. In a large population-based case-control study in Poland (2,386 cases, 2,502 controls), we investigated the association between breast cancer risk and 13 polymorphisms in 6 one-carbon metabolism genes (MTHFR, MTR, MTRR, CBS, SHMT1 and SLC19A1). Data suggested an association between a nonsynonymous change in the gene coding for methionine synthase (MTR D919G) and reduced breast cancer risk: OR (95% CI) = 0.84 (0.73-0.96) and 0.85 (0.62-1.15) for heterozygous and homozygote variant genotypes, respectively, compared with common homozygotes; p-trend = 0.01, false discovery rate = 0.14. We found no significant associations between other variants and breast cancer risk, including MTHFR A222V or E429A. Meta-analyses including published studies of MTHFR A222V (8,330 cases and 10,825 controls) and E429A (6,521 cases and 8,515 controls) supported the lack of an overall association; however, studies suggested an increase in risk among premenopausal women. In conclusion, this report does not support a substantial overall association between the evaluated polymorphisms in the one-carbon metabolism pathway and breast cancer risk.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / genetics
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism
  • Adult
  • Aged
  • Breast Neoplasms / epidemiology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Carbon / metabolism*
  • Case-Control Studies
  • Cystathionine beta-Synthase / genetics
  • Cystathionine beta-Synthase / metabolism
  • Female
  • Ferredoxin-NADP Reductase / genetics
  • Ferredoxin-NADP Reductase / metabolism
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Glycine Hydroxymethyltransferase / genetics
  • Glycine Hydroxymethyltransferase / metabolism
  • Humans
  • Logistic Models
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Meta-Analysis as Topic
  • Metabolic Networks and Pathways
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Middle Aged
  • Odds Ratio
  • Poland / epidemiology
  • Polymorphism, Single Nucleotide*
  • Reduced Folate Carrier Protein


  • Membrane Transport Proteins
  • Reduced Folate Carrier Protein
  • SLC19A1 protein, human
  • Carbon
  • methionine synthase reductase
  • Ferredoxin-NADP Reductase
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Glycine Hydroxymethyltransferase
  • Cystathionine beta-Synthase