Hypermethylation of the p14(ARF) gene in ulcerative colitis-associated colorectal carcinogenesis.

Abstract

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 (chi(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.

• Authors: Fumiaki Sato, Noam Harpaz, David Shibata, Yan Xu, Jing Yin, Yuriko Mori, Tong-Tong Zou, Suna Wang, Kena Desai, Anatoly Leytin, Florin M Selaru, John M Abraham, Stephen J Meltzer
• Journal: Cancer research (Cancer Res) Vol. 62 Issue 4 Pg. 1148-51 (Feb 15 2002) ISSN: 0008-5472 [Print] United States
• PMID: 11861396 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Sulfites
• Tumor Suppressor Protein p14ARF

Topics

• Base Sequence
• Colitis, Ulcerative (complications, genetics, metabolism)
• Colorectal Neoplasms (etiology, genetics, metabolism)
• DNA Methylation
• Humans
• Intestinal Mucosa (metabolism, pathology)
• Molecular Sequence Data
• Polymerase Chain Reaction
• Sequence Analysis, DNA (methods)
• Sulfites
• Tumor Suppressor Protein p14ARF (genetics)