Journal
MODERN PATHOLOGY
Volume 22, Issue 8, Pages 1121-1131Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/modpathol.2009.76
Keywords
dysplastic nodule; hepatocellular carcinoma; chromosomal instability; p21(WAF1/CIP1); telomere; hepatitis B virus
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Funding
- Korean Ministry of Science and Technology (MOST) [R13-2002-054-03004-0, FG06-11-04]
- Yonsei University College of Medicine [6-2007-0093]
- National Research Foundation of Korea [2005-0049245, 2007-0056176, R13-2002-054-03004-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Systemic analysis for chromosomal instability and inactivation of cell cycle checkpoints are scarce during hepatocarcinogenesis. We studied 24 patients with chronic B viral cirrhosis including 30 cirrhotic regenerative nodules, 35 low-grade dysplastic nodules, 15 high-grade dysplastic nodules, 7 dysplastic nodules with hepatocellular carcinoma foci, and 18 hepatocellular carcinomas. Eight normal livers were studied as the control group. Telomere length and micronuclei were detected by Southern blot and Feulgen-fast green dyeing technique, respectively, and p21(WAF1/CIP1) expression was studied by immunohistochemistry. Micronuclei > 1 per 3000 hepatocytes were found in 17% of low-grade dysplastic nodules, 87% of high-grade dysplastic nodules, and 100% of high-grade dysplastic nodules with hepatocellular carcinoma foci and hepatocellular carcinomas in contrast to those of all normal livers, and 90% of cirrhosis showed no micronuclei. The micronuclei index showed a gradual increase during hepatocarcinogenesis and there was a significant increase between cirrhosis and low-grade dysplastic nodules, low-grade dysplastic nodules and high-grade dysplastic nodules, and high-grade dysplastic nodules and hepatocellular carcinomas. Telomere length showed a gradual shortening during hepatocarcinogenesis and a significant reduction was found in high-grade dysplastic nodules (P = 0.024) and hepatocellular carcinomas (P = 0.031) compared with normal and cirrhotic livers. The micronuclei index was correlated with telomere shortening (P = 0.016). The p21(WAF1/CIP1) labeling index was significantly higher in cirrhosis than in normal livers (P = 0.024) and markedly decreased in low-grade dysplastic nodules, high-grade dysplastic nodules, and hepatocellular carcinomas compared with cirrhosis (P < 0.05). The p21(WAF1/CIP1) labeling index was associated with telomere length (P < 0.001) but not micronuclei index. This study shows that telomere shortening, chromosomal instability, and inactivation of p21(WAF1/CIP1) checkpoint function occur in low-grade dysplastic nodules as well as in high-grade dysplastic nodules, and their cooperation is considered to be critical for malignant transformation during hepatitis B virus associated-multistep hepatocarcinogenesis. Modern Pathology (2009) 22, 1121-1131; doi: 10.1038/modpathol.2009.76; published online 22 May 2009
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