The methylenetetrahydrofolate reductase (MTHFR) gene in colorectal cancer: role in tumor development and significance of allelic loss in tumor progression

Int J Gastrointest Cancer. 2001;30(3):105-11. doi: 10.1385/IJGC:30:3:105.


Background and aim: Folate deficiency predisposes to sporadic colorectal cancer (CRC). Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme and a polymorphism at position 677 (C677T), is associated with reduced enzyme activity. We investigated whether this functional polymorphism modulates the risk of developing CRC.

Methods: This was a retrospective case-control study. 136 unselected cases of sporadic CRC and 848 normal population controls were genotyped for the MTHFR C677T polymorphism. Tumor tissue was genotyped to assess loss of heterozygosity (LOH).

Results: MTHFR CT heterozygotes had a significantly increased risk of developing CRC (53.7% of CRC cases vs 38.4% of controls), odds ratio 1.86 (95% CI 1.3-2.7, p < 0.005). No increased cancer risk was observed in TT homozygotes. The MTHFR 'T' allele frequency was significantly higher in the cancer group (0.3713) as compared to controls (0.2900, p < 0.008). LOH at the MTHFR locus was observed in 18% of informative cancers, with exclusive loss of the variant 'T' allele, in all cases.

Conclusion: In this study of a homogenous northern European population, MTHFR CT heterozygotes had an almost two-fold increased risk of developing sporadic CRC. The exclusive pattern of MTHFR allele loss in cases of LOH, suggest that functional MTHFR activity within a tumor might play an important role in the survival and progression of a colonic neoplasm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / genetics*
  • Case-Control Studies
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics*
  • Disease Progression
  • Humans
  • Loss of Heterozygosity
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Polymorphism, Genetic / genetics
  • Retrospective Studies
  • Risk Factors


  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)