Several studies have showed the correlation of MTHFR gene polymorphisms with the risk of CRC [17–19]. Some previous studies suggested that the concentration of Vit B12 separately or in combination with other factors (e.g. folate), may have effect on different parts of the colon and rectal [20]. While folate is a vitamin B group involved in multiple biochemical processes, it acts as an important modulator of carcinogenesis. Folic acid is a pivotal nutrient in one-carbon cycle, which has a role in the synthesis of nucleotides and methylation reactions. Besides, MTHFR enzyme has an important role during synthesis, repair and methylation of DNA, as well as a role in circulating folate levels [21].
In the current study, we investigated the association of folate/vitamin B12 concentrations with MTHFR C677T polymorphisms in cancerous and precancerous colon lesions among Iranian patients. In this study, we did not observe an increase in C677T and 677TT MTHFR polymorphisms in CRC patients.
Previous studies on the association of C677T polymorphism and susceptibility to CRC, reported no constant consequences. Some studies suggested a protective effect of TT genotype for colon cancer, because during experiment, reduced risk of CRC progress was observed in TT individuals with a sufficient folate intake.
Several other studies suggested that 677TT MTHFR, the phenotype of valine amino acid, significantly depended on folate approachability. A recent in-vitro study on HCT116 colon carcinoma cells showed the association of valine amino acid (TT genotype) with increased genomic DNA methylation in an adequate folate level and a significantly lower DNA genomic methylation in folate deficiency. Thus, folate is a modifier of genotype effect. In fact, biochemical changes in the valine-containing enzyme is important, which shows the enzyme stabilization by the addition of 5-MTHF to the culture medium. Thus, folate might modify correlation between other SNPs and the CRC risk [22]. Migration and proliferation of cancer cell are two important events in cancer development. The main cause of death for cancer patients is metastasis, migration of cancerous cell from organ to other organs. A previous study showed that about 10 µM folic acid reduced the migration and proliferation of human cell lines (COLO-205, LoVo and HT-29) in CRC [23].
It has been shown that MTHFR 677TT genotype is one strong reason of decreased risk of proximal colon cancer. The site-specific analysis indicated the role of different molecular alterations in carcinogenesis in proximal and distal of colon and rectum. The more frequent genetic alterations in distal site are K-ras and P53 mutations as well microsatellite instability (MSI) is particularly in proximal site of colon in cancer [24, 25]. Totally, decreased risk of distal colon cancer, rectal cancer and proximal colon cancer have been reported to be associated with 677TT genotype. In the present study we did not find any increase of CRC risk in MTHFR 677TT genotype[15].
Some studies have shown a reduced risk of developing CRC with a TT genotype with a sufficient folate intake suggesting a protective effect [26, 27] although some other studies were not able to display a protective effect of the MTHFR 677TT genotype against CRC, even in high folate dietary intake [28, 29].
Some results have reported that the 677TT genotype could cause a considerable risk reduction of CRC. In high folate intake cases, the risk of CRC risk is reduced for both MTHFR 677CC and 677TT genotypes [30].
A meta-analysis study managed in twenty-five different countries, reported that different countries intake different sources of folate. Its results indicated that in Asia the 677TT genotype was admitted to a considerable CRC risk reduction [31].
A recent study observed a lower CRC risk through MTHFR 677TT genotype carriers of MTHFR C677T. There is an association between the MTHFR polymorphism and dietary methyl supply, but the relation remains inconsistent. Several studies reported the association of high-methyl diets like high folate dietary intake and low alcohol consumption with the protective effect of MTHFR 677TT genotype of the MTHFR C677T polymorphism [15, 32–35]. In contrast, another study reported that there is no association of folate status with the protective effect of MTHFR 677TT genotype compared with the CC/CT genotype. [19].