Methylenetetrahydrofolate reductase polymorphisms and risk of sporadic and hereditary colorectal cancer with or without microsatellite instability
Introduction
The human methylenetetrahydrofolate reductase (MTHFR) gene is located on chromosome 1p36.3 and encodes for a 656-amino-acid protein which acts as a homodimer [1]. MTHFR catalyses the formation of a methyl-donor, 5-methyltetrahydrofolate, acting in the remethylation of homocysteine to methionine [2]. MTHFR deficiency leads to an increased risk of clinical manifestations including developmental delay, premature vascular disease and neural-tube defects in newborn [3]. Reduced MTHFR enzyme activity increases the pool of methylenetetrahydrofolate which, in turn, reduces the pool of uracil. The misincorporation of uracil during DNA synthesis can result in DNA double strand breaks during excision repair processes [4]. Moreover, MTHFR deficiency might affect the level of DNA methylation due to reduced S-adenosylmethionine [5], [6]. It is widely accepted that both processes, DNA damage and DNA methylation, may be critical for the oncogenic transformation of human cells, providing a possible link between MTHFR and carcinogenesis.
Two common single nucleotide polymorphisms (SNPs) resulting in amino-acid changes (677C→T/Ala222Val and 1298A→C/Glu428Ala) have been described in MTHFR. The first variant reduces the enzyme activity and renders it more susceptible to heat inactivation [7]. With the second variant the MTHFR enzyme activity is reduced in homozygotes and, to a lesser extent, in heterozygotes [8]. Moreover, this variant might interact with the T allele at position 677 in reducing the plasma folate level [9]. The T allele at nucleotide 677 has been associated with a reduced risk of colorectal cancer [10], especially under adequate dietary folate intake and low alcohol consumption [11], [12]. More recently, an increased risk of CRC has been associated with the 677T/T genotype in older populations, especially with tumours showing microsatellite instability [13]. The C allele at nucleotide 1298 has shown to be associated with a decreased risk of adult acute lymphocytic leukaemia (ALL), but not with acute myeloid leukaemia (AML) [14]. In colorectal cancer a slightly reduced risk with the 1298 C allele, independent from the 677 polymorphism, has been reported [15].
In the present study we analysed a series of 287 patients with colorectal cancer for both amino-acid-changing variants. Analyses separated for subtypes of cases, as sporadic and hereditary cases, might enhance the detection of effects of low penetrance genes. Moreover, hypermethylation of the hMLH1 promoter is frequently found in hMLH1-deficient MSI-H tumours [16], thus, providing a possible link between those tumours and genes affecting methylation capacity. We estimated the relative risk associated with each of the different genotypes for groups of patients with sporadic disease, with suspected/verified hereditary disease and for patients with tumours exhibiting or not exhibiting high levels of microsatellite instability (MSI-H). In contrast to some of the previously reported results no significant differences for the relative risk were identified for any of the genotypes or alleles in any of the groups of patients investigated.
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Patients
Peripheral blood and tumour samples from 227 patients with sporadic primary colorectal cancer and 60 patients fulfilling the Bethesda guidelines for the hereditary non-polyposis colorectal cancer (HNPCC) syndrome were collected at the time of surgery. All patients originated from Saxony, Germany. The Bethesda guidelines were developed to aid in the identification of patients with HNPCC [17], including (B1) patients of families with at least three members affected with histological verified
Results
Among the 287 patients diagnosed with colorectal cancer, the frequency of the MTHFR 677T allele (32.4%) was almost identical to the 34.0% found in 346 healthy controls. A similar correspondence was seen for the 1298C allele with 31.9% in tumour patients versus 34.0% in controls. The frequencies of the different genotypes for both variants did not differ significantly between the two populations, although the heterozygous 677C/T genotype was less frequent among tumour patients (41.8 versus 45.9%
Discussion
In the present study, we have analysed patients with sporadic or hereditary colorectal cancer for two common amino acid-changing polymorphisms in the MTHFR gene. We did not identify an association between the two groups of patients and the alleles, genotypes or the combined genotypes. Our results corroborate recent findings of a lack of association with colorectal adenomas and hyperplastic polyps [19], [20], [21], but disagree with those showing that the MTHFR 677T/T genotype is associated with
Acknowledgements
We thank Ms. M. Biesold for excellent technical assistance.
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