DNA methylation as an intermediate biomarker in colorectal cancer

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Abstract
Several studies have suggested that DNA hypomethylation is an early step in colorectal carcinogenesis. However, it is not clear at which stage in carcinogenesis this hypomethylation occurs, what promotes it, the extent to which it can be reversed and the consequences of such reversal in affecting tumour development. In an attempt to address some of these questions, we studied three groups of subjects with similar age and gender distributions: a group of 12 patients with colorectal carcinomas; a group of 12 patients with colorectal adenomas; and a group of eight healthy control subjects. Two experimental protocols were employed. In the first protocol, intrinsic DNA methylation was evaluated in neoplastic and in normal-appearing rectal mucosa of patients with colonic carcinomas or adenomas, compared with a group of healthy controls. In the second protocol, we examined, in a prospective and controlled fashion, the effect of folic acid supplementation (10 mg/day) on the degree of DNA methylation of rectal mucosa from those same patients after removal of the neoplasms. The degree of intrinsic DNA methylation was assessed on the basis of the capacity of the DNA isolates to serve as methyl acceptors in in vitro incubations that contained DNA methylase and [3H-methyl] S-adenosylmethionine. Intrinsic DNA methylation was significantly lower in carcinomas than in adenomas (P < 0.005). In addition, normal-appearing rectal mucosa from patients with carcinomas was significantly less methylated than in healthy controls (P < 0.005); the mean value found in the latter was also greater than the value observed in patients with adenomas, but not significantly so (P > 0.05). Patients with resected neoplasms who received folk acid supplementation for 6 months had a marked increase in the degree of intrinsic DNA methylation in the rectal mucosa (P < 0.002). Three months after cessation of treatment, DNA methylation decreased substantially (P < 0.05), but remained significantly greater than baseline values (P < 0.02). In contrast, DNA methylation values remained stable throughout the study in placebo-treated patients (P = 0.40). Our study demonstrates that global DNA hypomethylation occurs in normal rectal mucosa from patients with colorectal neoplasms as compared with controls, and that it was significantly reduced with pharmacological doses of folk add. It remains to be determined whether the risk of tumour recurrence is affected as well.

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