Hypermethylation of the pl 6 INK 4 a Promoter in Colectomy Specimens of Patients with Long-standing and Extensive Ulcerative Colitis 1 ' 2

Functional inactivation of the />/r/%f"'' gene has been reported to be involved in the development of a variety of human malignancies. Recent evidence shows that transcriptional silencing as a consequence of hypermethylation of CpG islands is the predominant mechanism of pI6'^K4a gene inactivation in sporadic colon cancer. This study sought to identify the significance of pI6INK4" methylation in the colonie epithelium of patients with long-standing ulcerative colitis. A total of 89 tissue samples was retrieved from three colectomy specimens. A methylation-specific PCR assay was applied. The methylation status was compared with his tolÃ3gica) findings and the flow cytometrically determined DNA index. Hypermethylation of the pl6INK4a promoter region was detected in 12.7% of samples that were negative for dysplasia. However, 70.0% of samples with dysplasia and all of the samples with carcinomatous lesions revealed hypermethylation. Hypermethylation of the pì6lfiK4agene promoter was detected already in 40% of specimens with lesions indefinite for dysplasia and in 13.7% of samples with exclusively diploid cell populations. These results suggest that hypermethylation of thep/o'**'*1 promoter region is a frequent and early occurring event during the process of neoplastic pro gression in ulcerative colitis.

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