Hypermethylation of the p14ARF gene in ulcerative colitis-associated colorectal carcinogenesis

Fumiaki Sato, Yan Xu, Jing Yin, Yuriko Mori, Tong Tong Zou, Suna Wang, Kena Desai, Florin M. Selaru, John M. Abraham, Stephen J. Meltzer, Fumiaki Sato, Yan Xu, Jing Yin, Yuriko Mori, Tong Tong Zou, Suna Wang, Kena Desai, Florin M. Selaru, John M. Abraham, Stephen J. MeltzerNoam Harpaz, Anatoly Leytin, David Shibata

Research output: Contribution to journalArticlepeer-review

Abstract

The p14ARF protein directly inhibits the MDM-2 oncoprotein, which mediates degradation of the p53 protein. It has been shown that p14ARF expression is frequently down-regulated by p14ARF gene hypermethylation in colorectal cancer. To determine whether p14ARF inactivation was involved in ulcerative colitis (UC)-associated carcinogenesis, the frequency and timing of p14ARF 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 p14ARF gene methylation. p14ARF 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 p14ARF methylation (X2 test: P = 0.0003). Bisulfite sequencing was used to analyze 28 CpGs of p14ARF 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 p14ARF is a relatively common early event in UC-associated carcinogenesis. p14ARF offers potential as a biomarker for the early detection of cancer or dysplasia in UC. Finally, analyses of p14ARF methylation in other organs should explore not only frank cancers but other premalignant lesions.

Original languageEnglish (US)
Pages (from-to)1148-1151
Number of pages4
JournalCancer Research
Volume62
Issue number4
StatePublished - Feb 15 2002
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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