Gene promoter methylation in colorectal cancer and healthy adjacent mucosa specimens: correlation with physiological and pathological characteristics, and with biomarkers of one-carbon metabolism

摘要

We evaluated the promoter methylation levels of the APC, MGMT, hMLH1, RASSF1A and CDKN2A genes in 107 colorectal\udcancer (CRC) samples and 80 healthy adjacent tissues. We searched for correlation with both physical and pathological\udfeatures, polymorphisms of folate metabolism pathway genes (MTHFR, MTRR, MTR, RFC1, TYMS, and DNMT3B),\udand data on circulating folate, vitamin B12 and homocysteine, which were available in a subgroup of the CRC patients.\udAn increased number of methylated samples were found in CRC respect to adjacent healthy tissues, with the exception\udof APC, which was also frequently methylated in healthy colonic mucosa. Statistically significant associations were found\udbetween RASSF1A promoter methylation and tumor stage, and between hMLH1 promoter methylation and tumor location.\udIncreasing age positively correlated with both hMLH1 and MGMT methylation levels in CRC tissues, and with APC\udmethylation levels in the adjacent healthy mucosa. Concerning gender, females showed higher hMLH1 promoter methylation\udlevels with respect to males. In CRC samples, the MTR 2756AG genotype correlated with higher methylation levels\udof RASSF1A, and the TYMS 1494 6bp ins/del polymorphism correlated with the methylation levels of both APC and hMLH1.\udIn adjacent healthy tissues, MTR 2756AG and TYMS 1494 6bp del/del genotypes correlated with APC and MGMT promoter\udmethylation, respectively. Low folate levels were associated with hMLH1 hypermethylation. Present results support the\udhypothesis that DNA methylation in CRC depends from both physiological and environmental factors, with one-carbon\udmetabolism largely involved in this process.