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Relationship of the methylenetetrahydrofolate reductase C677T polymorphism with microsatellite instability and promoter hypermethylation in sporadic colorectal cancer
Alessandra D. Clarizia1, Luciana Bastos-Rodrigues1, Heloísa B. Pena1, Charles Anacleto1,
Benedito Rossi2, Fernando A. Soares2, Ademar Lopes2, José Cláudio C. Rocha2,
Otávia Caballero4, Anamaria Camargo3, Andrew J.G. Simpson4 and Sérgio D.J. Pena1
1Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais,
Belo Horizonte, MG, Brasil
2Hospital A.C. Camargo, São Paulo, SP, Brasil
3Instituto Ludwig de Pesquisa sobre o Câncer, São Paulo, SP, Brasil
4Ludwig Institute for Cancer Research, New York, NY, USA
Corresponding author: S.D.J. Pena
Genet. Mol. Res. 5 (2): 315-322 (2006)
Received January 27, 2006
Accepted March 28, 2006
Published May 17, 2006

ABSTRACT. The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with the expression of a thermolabile enzyme with decreased activity that influences the pool of methyl-donor molecules. Several studies have reported an association between C677T polymorphism and susceptibility to colorectal cancer (CRC). Considering that methylation abnormalities appear to be important for the pathogenesis of CRC, we examined the correlation between the genotype of the MTHFR C677T polymorphism, hypermethylation of the promoter region of five relevant genes (DAPK, MGMT, hMLH1, p16INK4a, and p14ARF), and microsatellite instability, in 106 patients with primary CRCs in Brazil. We did not find significant differences in the genotypic frequencies of the MTHFR C677T polymorphism when one or more loci were hypermethylated. However, we did find a significant excess of 677TT individuals among patients with CRC who had microsatellite instability. This strong association was independent of the methylation status of hMLH1 and of the biogeographical genomic ancestry of the patients. Although the mechanism responsible for the link between the C677T polymorphism and microsatellite instability was not apparent, this finding may provide a clue towards a better understanding of the pathogenesis of microsatellite instability in human colorectal cancer.

Key words: Methylenetetrahydrofolate reductase, MTHFR, C677T polymorphism, Microsatellite instability, Hypermethylation, Colorectal cancer


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