Promoter Methylation of INK4a/ARF As Detected in Bile-Significance for the Differential Diagnosis in Biliary Disease

Purpose: There is a need to enhance endobiliary cytotechniques by molecular marker lesions. This is of special significance for patients with primary sclerosing cholangitis, a disease predisposing for the development of cholangiocarcinoma. The INK4a/ADP ribosylation factor (ARF) locus encodes two tu...

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Published in:	Clinical cancer research Vol. 9; no. 5; pp. 1773 - 1778
Main Authors:	KLUMP, Bodo, HSIEH, Chih-Jen, DETTE, Stephan, HOLZMANN, Karlheinz, KIESSLICH, Ralf, JUNG, Michael, SINN, Udo, ORTNER, Marianne, PORSCHEN, Rainer, GREGOR, Michael
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-05-2003
Subjects:	Adult Aged Bile Duct Neoplasms - diagnosis Bile Duct Neoplasms - genetics Bile Duct Neoplasms - metabolism Bile Ducts, Intrahepatic Biological and medical sciences Biomarkers, Tumor - metabolism Cholangiocarcinoma - diagnosis Cholangiocarcinoma - genetics Cholangiocarcinoma - metabolism Choledocholithiasis - diagnosis Choledocholithiasis - genetics Choledocholithiasis - metabolism Cyclin-Dependent Kinase Inhibitor p16 - genetics Diagnosis, Differential DNA Methylation DNA, Neoplasm - genetics Gallbladder Diseases - diagnosis Gallbladder Diseases - genetics Gallbladder Diseases - metabolism Gastroenterology. Liver. Pancreas. Abdomen Gene Silencing Humans Liver. Biliary tract. Portal circulation. Exocrine pancreas Medical sciences Middle Aged Prognosis Promoter Regions, Genetic - genetics Reverse Transcriptase Polymerase Chain Reaction Survival Rate Tumor Suppressor Protein p14ARF - genetics Tumors Human Transcription promoter Cholangitis Hepatic disease Malignant tumor Biliary tract disease Differential diagnostic Infection Malignant cholangioma Bacteriosis Digestive diseases Diagnosis Methylation Bile Tumor suppressor gene
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Summary:	Purpose: There is a need to enhance endobiliary cytotechniques by molecular marker lesions. This is of special significance for patients with primary sclerosing cholangitis, a disease predisposing for the development of cholangiocarcinoma. The INK4a/ADP ribosylation factor (ARF) locus encodes two tumor suppressor genes: p16INK4a and p14ARF . p16INK4a has been shown to be of major significance in cholangiocarcinoma. Experimental Design: In an effort to evaluate the potential diagnostic role of p16INK4a and p14ARF promoter methylation in biliary disease, endoscopical obtained bile specimens of 71 patients were analyzed (26 choledocholithiasis, 6 with normal results, 23 bile duct carcinoma, 5 gall bladder carcinoma). Eleven patients with primary sclerosing cholangitis were enrolled. Results: Merely 6% of specimens (2 of 32) obtained from patients without evidence for malignant biliary disease but 53.5% of malignancies (15 of 28) showed p16 promoter methylation (p14: 3 and 46.2%, respectively). The concordance of methylation rates detected in either bile or tissue specimens was high. In primary sclerosing cholangitis, a similar prevalence of methylation was detected as in malignant disease. Conclusions: This study demonstrates: ( a ) a high frequency and specificity of INK4a/ARF methylation in malignant biliary disease compared with mere cholangitis; and ( b ) the capability to detect these alterations reliably in endoscopically obtained bile. Thus, INK4a/ARF’s promoter methylation status represents a candidate marker for the endoscopic diagnosis of biliary disease.
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ISSN:	1078-0432 1557-3265