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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
 Journal of Hepatology 
Issue Date
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. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실)
Yonsei Authors
김경식(Kim, Kyung Sik) ORCID logo https://orcid.org/0000-0001-9498-284X
김명수(Kim, Myoung Soo) ORCID logo https://orcid.org/0000-0002-8975-8381
박영년(Park, Young Nyun) ORCID logo https://orcid.org/0000-0003-0357-7967
엄태희(Um, Tae Hee)
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