Accelerated age-related CpG island methylation in ulcerative colitis

CpG island hypermethylation is a mechanism of gene silencing that can be us urped by neoplastic cells to inactivate undesirable genes. In the colon, hy permethylation often starts in normal mucosa as a function of age and Is ma rkedly increased in cancer. To test the hypothesis that subjects at increas ed risk of colon canter have higher levels of methylation in their nonneopl astic mucosa, we studied methylation patterns of five genes in the normal a nd dysplastic mucosa of patients with ulcerative colitis (UC), a condition associated with a marked increased risk of colon cancer. One gene (Mlh1) wa s unmethylated in all tissues examined, All four remaining genes had low bu t detectable levels of methylation in the epithelium of UC patients without evidence of dysplasia, and this methylation was not different from non-UC controls. BS contrast, all four genes were highly methylated in dysplastic epithelium from high-grade dysplasia (HGD)/ cancer patients with UC; methyl ation in HGD versus controls averaged 40.0% versus 7.4% (P = 0.00003) for E R, 44.0% versus 3.0% (P < 0.00003) for MYOD, 9.4% versus 2.4% (P = 0.03) fo r p16 exon 1, and 57.5% versus 30.6% (P = 0.01) fur CSPG2, Importantly, thr ee of the four genes were also highly methylated in the normal appearing (n ondysplastic) epithelium from these same HGD/cancer patients, indicating th at methylation precedes dysplasia and is widespread in these patients. Comp ared with controls, methylation averaged 20.1% versus 7.2% (P = 0.07) for E R, 18.4% versus 3.0% (P < 0.008) for MYOD, and 7.9% versus 2.4% (P = 0.007) for p16 exon 1. These results are consistent with the hypothesis that age- related methylation marks (and may lead to) the field defect that reflects acquired predisposition to colorectal neoplasia, Furthermore, the data sugg est that chronic inflammation is associated with high levels of methylation , perhaps as a result of increased cell turnover, and that UC can be viewed as resulting in premature aging of colorectal epithelial cells.