Carcinogenesis Advance Access originally published online on July 16, 2008
Carcinogenesis 2008 29(10):1901-1910; doi:10.1093/carcin/bgn170
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Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas
1 Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan
2 Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
3 Department of Leukemia, The University of Texas at M.D. Anderson Cancer Center, Houston, TX 77030, USA
4 Department of Gastroenterological Surgery
5 Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan
6 Department of Neurosurgery, Nagoya University School of Medicine, Showa-ku, Nagoya 466-8550, Japan
7 Department of Bioinformatics and Computational Biology, The University of Texas at M.D. Anderson Cancer Center, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +81 52 764 2993; Fax: +81 52 764 2993; Email: ykondo{at}aichi-cc.jp
Hepatocellular carcinoma (HCC) most commonly arises from chronic inflammation due to viral infection, as a result of genetic and epigenetic abnormalities. A global picture of epigenetic changes in HCC is lacking. We used methylated CpG island amplification microarrays (MCAMs) to study 6458 CpG islands in HCC and adjacent preneoplastic tissues [chronic hepatitis (CH) or liver cirrhosis (LC)] in comparison with normal liver tissues where neither viral infection nor hepatitis has existed. MCAM identified 719 (11%) prominent genes of hypermethylation in HCCs. HCCs arising from LC had significantly more methylation than those arising from CH (1249 genes or 19% versus 444 genes or 7%, P < 0.05). There were four patterns of aberrant methylation: Type I (4%, e.g. matrix metalloproteinase 14) shows a substantially high methylation level in adjacent tissue and does not increase further in cancer. Type II (55%, e.g. RASSF1A) shows progressively increasing methylation from adjacent tissue to HCC. Type III (4%, e.g. GNA14) shows decreased methylation in adjacent tissue but either similar or increased methylation in HCC. Type IV (37%, e.g. CDKN2A) shows low levels of methylation in normal tissue and adjacent tissue but high levels in HCC. These DNA methylation changes were confirmed by quantitative pyrosequencing methylation analysis in representative 24 genes and were analyzed for correlation with clinicopathological parameters in 38 patients. Intriguingly, methylation in the Type IV genes is characteristic of moderately/poorly differentiated cancer. Our global epigenome analysis reveals distinct patterns of methylation that are probably to represent different pathophysiologic processes in HCCs.
Abbreviations: CH, chronic hepatitis; DNMT, DNA methyltransferase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LC, liver cirrhosis; MCA, methylated CpG island amplification; MCAM, methylated CpG island amplification microarray; MMP14, matrix metalloproteinase 14; PCR, polymerase chain reaction; TSS, transcription start sites
Received February 11, 2008; revised July 9, 2008; accepted July 10, 2008.
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