title: 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.affiliation: Gastroenterology Division, Department of Medicine, University of Maryland School of Medicine and Gastroenterology Service, Baltimore, Maryland 21201, USA.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sato
authors.forename: Noam
authors.initials: N
authors.lastname: Harpaz
authors.forename: David
authors.initials: D
authors.lastname: Shibata
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Jing
authors.initials: J
authors.lastname: Yin
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Mori
authors.forename: Tong-Tong
authors.initials: TT
authors.lastname: Zou
authors.forename: Suna
authors.initials: S
authors.lastname: Wang
authors.forename: Kena
authors.initials: K
authors.lastname: Desai
authors.forename: Anatoly
authors.initials: A
authors.lastname: Leytin
authors.forename: Florin M
authors.initials: FM
authors.lastname: Selaru
authors.forename: John M
authors.initials: JM
authors.lastname: Abraham
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
mesh_terms: D001483:Base Sequence; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA / Q000379:methods; D013447:Sulfites; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
chemical_list: D013447:Sulfites; D025803:Tumor Suppressor Protein p14ARF