Transcriptional silencing of tumor suppressor genes by hypermethylation of CpG islands located in the promoter region is very common in human colorectal cancer. Dietary folate/vitamin B12 intake and MTHFR C677T genotype was suggested to protect against colorectal cancer. However, only a few studies have addressed the joint effects of circulating levels of folate/vitamin B12 and the MTHFR C677T genotype on the risk of epigenetic inactivation of specific tumor suppressor genes in CRC patients.
A research article to be published on 21 June 2008, in the World Journal of Gastroenterology addresses this question. The research team led by Prof. Naghibalhossaini from Department of Biochemistry of Shiraz University of Medical Sciences investigated the association between serum folate/vitamin B12, MTHFR C677T genotype, and promoter methylation of three tumor-associated genes in solid tumors among sporadic CRC patients.
They found that 29.1 % of cases had tumors with at least one methylated gene promoter. In case-case comparison, no significant association was found between methylation in tumors and any single genotype. However, in comparison to controls with the CC genotype, an increased risk of tumor methylation was associated with the CT genotype (OR = 2.5; 95%CI, 1.1 – 5.6). In case-case comparisons, folate/vitamin B12 was positively associated with tumor methylation. Adjusted odds ratios for tumor methylation in cases with high (above median) versus low (below median) serum folate/vitamin B12 levels were 4.9 (95%CI, 1.4 – 17.7), and 3.9 (95%CI, 1.1 – 13.9), respectively. The frequency of methylated tumors was significantly higher in high methyl donor than low methyl donor group, especially in those with MTHFR CT (p = 0.01), and CT/TT (P = 0.002) genotypes but, not in those with the CC genotype (P = 1.0).
The results from this study indicate that high concentrations of serum folate/vitamine B12 are associated with the risk of promoter methylation in tumor-specific genes, and this relationship is modified by MTHFR C677T genotypes. These results support other recent reports that high folate and vitamin B12 status might serve as risk factors for CRC.