MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer

Eur J Hum Genet. 2009 May;17(5):629-35. doi: 10.1038/ejhg.2008.239. Epub 2009 Jan 21.


Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome is characterized by inactivating germline mutations in DNA mismatch repair genes resulting in an increased risk of developing an epithelial malignancy. There is considerable variability in disease expression observed in this syndrome, which is thought to be due to a combination of genetic and environmental factors. Alterations in the kinetics of methylene tetrahydrofolate reductase (MTHFR) due to the presence of polymorphisms in the MTHFR gene have been associated with an increased risk of colorectal cancer (CRC). Two common single nucleotide polymorphisms (SNPs) located within the MTHFR gene, 677 C>T and 1298 A>C, that alter the function of the encoded protein have been the focus of many studies on CRC risk outside the context of an inherited predisposition to disease. In this report, a total of 417 HNPCC participants were genotyped for the 677 C>T and 1298 A>C SNPs to determine whether there exists an association with the age of disease onset of CRC. Genotyping of both SNPs was performed by TaqMan(R) assay technology. Associations in disease risk were further investigated using Kaplan-Meier survival analysis and Cox hazard regression. The average ages of disease diagnosis were found to be different between individuals harbouring either one of the MTHFR polymorphisms. Both Kaplan-Meier and Cox hazard regression analyses revealed a more complex relationship between the two polymorphisms and the age of CRC onset. The Kaplan-Meier survival analysis revealed that compound heterozygotes for the two SNPs developed CRC 10 years later compared with those carrying only wild-type alleles.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Alleles
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Polymorphism, Single Nucleotide*


  • Methylenetetrahydrofolate Reductase (NADPH2)