title: Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas.
abstract: 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.
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan.
authors.forename: Wentao
authors.initials: W
authors.lastname: Gao
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.forename: Lanlan
authors.initials: L
authors.lastname: Shen
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sano
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamao
authors.forename: Atsushi
authors.initials: A
authors.lastname: Natsume
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Goto
authors.forename: Motokazu
authors.initials: M
authors.lastname: Ito
authors.forename: Hideki
authors.initials: H
authors.lastname: Murakami
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D053263:Gene Regulatory Networks; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D051153:Wnt Proteins / Q000502:physiology
chemical_list: D051153:Wnt Proteins