Polymorphisms in genes involved in folate metabolism and plasma DNA methylation in colorectal cancer patients.
Aberrant methylation of promoter regions associated with gene silencing is one of the major mechanisms underlying the inactivation of tumor suppressor genes in carcinogenesis. Previous studies have proposed that methylated DNA from tumor cells is released into the circulation and might be widely used as a marker for non-invasive tumor detection. Catalytic activities of folate metabolism-related enzymes and adequate synthesis of methyl donors are important elements for the cellular methylation reaction. In the present study, we sought to determine the following: i) genotype frequencies of MTHFR and MTR involved in folate metabolism in cases and cancer-free controls; and ii) the methylation status of three candidate genes (p16INK4A, p73 and hMLH1) in plasma related to the folate and homocysteine levels. From genotype frequency analysis, individuals homozygous for the MTHFR 677TT genotype had a significantly reduced risk of developing colorectal cancer compared with those harboring the MTHFR 677CC genotype (OR, 0.206; 95% CI, 0.070-0.604; P=0.005), and had a lower plasma folate concentration than those with the MTHFR 677CC+CT genotype (P<0.05). Using methylation-specific PCR, p73 was shown to be more frequently methylated in the high folate group [50% (8 of 16)] than in the medium [16.7% (3 of 18)] or low folate subgroups [11.1% (2 of 18)]. In conclusion, subjects with the variant MTHFR 677TT genotype appeared to have a significantly lower risk for colorectal cancer than those with the MTHFR 677CC genotype, and the methylation status of circulating p73 genomic DNA was substantially altered by the plasma folate level.