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Hypermethylation of the p14^ARF Gene in Ulcerative Colitis-associated Colorectal Carcinogenesis¹

Gastroenterology Division, Department of Medicine, University of Maryland School of Medicine and Gastroenterology Service, Department of Medicine, Baltimore Veterans Administration Hospital Baltimore, Maryland 21201 [F. S., Y. X., J. Y., Y. M., T-T. Z., S. W., K. D., F. M. S., J. M. A., S. J. M.]; Department of Pathology, The Mount Sinai School of Medicine, New York, New York 10029 [N. H., A. L.]; and Division of Surgical Oncology, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201 [D. S.]

The p14^ARF protein directly inhibits the MDM-2 oncoprotein, which mediates degradation of the p53 protein. It has been shown that p14^ARF expression is frequently down-regulated by p14^ARF gene hypermethylation in colorectal cancer. To determine whether p14^ARF inactivation was involved in ulcerative colitis (UC)-associated carcinogenesis, the frequency and timing of p14^ARF methylation was investigated in four different histological stages of UC-associated carcinogenesis. Methylation-specific PCR and bisulfite sequencing were used to determine the prevalence of p14^ARF gene methylation. p14^ARF methylation was observed in 19 of 38 (50%) adenocarcinomas, 4 of 12 (33%) dysplasias, and 3 of the 5 (60%) nonneoplastic UC mucosae. In contrast, 3 of 40 (3.7%) normal tissues showed p14^ARF methylation (² test: P = 0.0003). Bisulfite sequencing was used to analyze 28 CpGs of p14^ARF gene in 20 samples. The number of methylated CpGs ranged from 0 to 4, 0 to 20, and 0 to 28 in the normal, dysplastic, and carcinomatous samples, respectively (Kruskall-Wallis test: P = 0.0005). Densely methylated alleles were detected only in carcinomas by bisulfite sequencing. In conclusion, our data suggest that methylation of p14^ARF is a relatively common early event in UC-associated carcinogenesis. p14^ARF offers potential as a biomarker for the early detection of cancer or dysplasia in UC. Finally, analyses of p14^ARF methylation in other organs should explore not only frank cancers but other premalignant lesions.

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