ACF as a marker for colon carcinogensis in patients with ulcerative colitis and its gene analysis

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Aim: we identified aberrant crypt foci (ACF) in patients with ulcerative colitis (IJC), investigated various gene alterations and clarified the significance of ACF as a biomarker in colon carcinogenesis. Methods and Results: (1) Twenty-eight patients with UC were enrolled. We observed rectal area using magnifying endoscopy with the aid of methylene blue staining as previously we described (N Engl J Med, 1998). We found ACF lesions in 27 patients out of 28. ACF in UC patients showed obscure crypt lining as compared to ACF in non-UC patients. The number of ACF in patients with dysplasia was significantly more than that without dysplasia. (2) There were positive correlations between dysplasia and ACF number or duration of disease. (3) Essentially there were no mutations of APC and K-ras in ACF and dysplasia as revealed by In vitro synthesized protein (IVSP) assay and 2-step PCR RFLP respectively. (4) Very low rates of MSI were detected in ACF and dysplasia by PCR SSCP method. (5) There was no p53 mutation in ACF although it was frequently positive in dysplasia and cancer by PCR SSCP method. Immunostaining for p53 also revealed no accumulation of p53 in ACF although it was frequently accumulated in dysplasia and cancer. (6) Hypermethylation of p16 was highly positive in ACF, dysplasia and cancer by bisulfite method. Conclusion: It was demonstrated that ACF are viable marker for detection of dysplasia and subsequent cancer. It was also strongly suggested that ACF develop by p16 hypermethylation and proceed to dysplasia by p53 mutation.