One-carbon metabolism and CpG island methylator phenotype status in incident colorectal cancer: a nested case-referent study

We related prediagnostic plasma folate, vitamin B12, and total homocysteine concentrations, and the MTHFR 677C > T and 1298A > C polymorphisms, to the risk of colorectal cancer with and without the CpG island methylator phenotype (CIMP). This was a nested case-referent study of 190 cases and double, matched referents from the large, population-based Northern Sweden Health and Disease Study. Using archival tumor tissue, promoter methylation in an eight-gene panel was analyzed by MethyLight. A reduced risk of CIMP-low/CIMP-high CRC (a parts per thousand yen1 gene methylated) was observed in subjects with very low plasma folate concentrations [multivariate odds ratio 2.96 (95% CI 1.24-7.08) for quintiles two to five versus one (lowest)]. With the exception of a reduced risk in MTHFR 677 TT-homozygotes, none of the other one-carbon variables were associated with the risk of CIMP-low/CIMP-high CRC. For CIMP-negative CRC, only the MTHFR polymorphisms were statistically significantly related to risk, inversely for 677C > T and positively for 1298A > C, but a tendency toward a reduced risk was observed in subjects with an adequate methyl availability, combining the plasma variables [multivariate odds ratio 0.61 (95% CI 0.32-1.15)]. Though limited by low power, these findings suggest the possibility of different roles for one-carbon metabolism in different pathways of colorectal tumorigenesis.