Hypermethylation of the p16^INK4a Promoter in Colectomy Specimens of Patients with Long-standing and Extensive Ulcerative Colitis^1,2

Functional inactivation of the p16^INK4a 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 p16^INK4a gene inactivation in sporadic colon cancer. This study sought to identify the significance of p16^INK4a methylation in the colonic 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 histological findings and the flow cytometrically determined DNA index. Hypermethylation of the p16^INK4a 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 p16^INK4a gene 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 the p16^INK4a promoter region is a frequent and early occurring event during the process of neoplastic progression in ulcerative colitis.