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Aberrant CpG island hypermethylation in dysplastic nodules and early HCC of hepatitis B virus-related human multistep hepatocarcinogenesis

 Tae-Hee Um  ;  Haeryoung Kim  ;  Bong-Kyeong Oh  ;  Myoung Soo Kim  ;  Kyung Sik Kim  ;  Guhung Jung  ;  Young Nyun Park 
 JOURNAL OF HEPATOLOGY, Vol.54(5) : 939-947, 2011 
Journal Title
Issue Date
Adenomatous Polyposis Coli Protein/genetics ; Adenomatous Polyposis Coli Protein/metabolism ; Adult ; Aged ; Carcinoma, Hepatocellular*/genetics ; Carcinoma, Hepatocellular*/metabolism ; Carcinoma, Hepatocellular*/virology ; Cell Transformation, Neoplastic ; Cell Transformation, Viral ; CpG Islands/genetics* ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclooxygenase 2/genetics ; Cyclooxygenase 2/metabolism ; DNA Methylation/genetics* ; Female ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic*/complications ; Hepatitis B, Chronic*/genetics ; Hepatitis B, Chronic*/virology ; Humans ; Liver Neoplasms*/genetics ; Liver Neoplasms*/metabolism ; Liver Neoplasms*/virology ; Male ; Middle Aged ; Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling Proteins/genetics ; Suppressor of Cytokine Signaling Proteins/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
Methylation ; Hepatitis B virus ; Hepatocellular carcinoma ; Multistep hepatocarcinogenesis
BACKGROUND & AIMS: The concept of multistep hepatocarcinogenesis has been well-established, and an accumulation of methylating events has recently been demonstrated; however, the methylation status of low-grade dysplastic nodules (LGDN), high-grade dysplastic nodules (HGDN), and the recently introduced early hepatocellular carcinoma (eHCC) in hepatitis B virus (HBV)-related hepatocarcinogenesis has not yet been studied. METHODS: One hundred thirty-three DNA samples (45 cirrhotic nodules, 29 LGDNs, 13 HGDNs, 14 eHCCs, and 32 progressed HCCs (pHCCs)) from HBV-infected resected livers were subjected to MethyLight analysis for nine CpG island loci (APC, RASSF1A, SOCS1, P16, COX2, SPRY2, PTEN, GNMT, and ERK), and COX2, RASSF1A, and SOCS1 protein expression status was analyzed by immunohistochemistry. The methylation status of each sample was correlated with the clinicopathological features. RESULTS: APC, RASSF1A, and SOCS1 were methylated in 20 (44.4%), 25 (55.6%), and 13 (28.9%) of 45 cirrhosis samples, and APC (p=0.0008) and SOCS1 (p=0.0187) methylation were more frequent in dysplastic nodules and HCCs. APC (p=0.001) and RASSF1A (p=0.019) methylation levels were significantly increased from cirrhosis to LGDN. SOCS1 methylation gradually increased along multistep hepatocarcinogenesis, peaked at eHCC and decreased significantly in pHCCs (p=0.039). By contrast, p16 and COX2 was only methylated in dysplastic nodules and HCCs, with a stepwise increase up to pHCCs. As a whole, the frequency of methylation was highest in eHCCs. A stepwise decrease in COX2, RASSF1A, and SOCS1 protein expression was demonstrated. CONCLUSIONS: A general stepwise increase in methylating events is seen during HBV-related multistep hepatocarcinogenesis, and epigenetic changes may occur predominantly in the earlier stages of HCC development.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Sik(김경식) ORCID logo https://orcid.org/0000-0001-9498-284X
Kim, Myoung Soo(김명수) ORCID logo https://orcid.org/0000-0002-8975-8381
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Um, Tae Hee(엄태희)
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