title: Unique association between global DNA hypomethylation and chromosomal alterations in human hepatocellular carcinoma.
abstract: Global DNA hypomethylation is a characteristic feature of cancer cells that closely associates with chromosomal instability (CIN). However, the association between these characteristics during hepatocarcinogenesis remains unclear. Herein, we determined the relationship between hypomethylation and CIN in human hepatocellular carcinoma (HCC) by analyzing 179 HCCs, 178 matched non-tumor livers and 23 normal liver tissues. Hypomethylation at three different repetitive DNA (rDNA) sequences and hypermethylation of 12 CpG loci, including 11 tumor suppressor gene (TSG) promoters, were quantified using MethyLight or combined bisulfite restriction analysis. Fractional allelic loss (FAL) was used as a marker for CIN, calculated by analyzing 400 microsatellite markers. Gains and losses at each chromosome were also determined using semi-quantitative microsatellite analysis. The associations between rDNA hypomethylation and FAL, as well as between TSG hypermethylation and FAL were investigated. Significantly more hypomethylation was observed in HCC tissues than in normal liver samples. Progression of hypomethylation during carcinogenesis was more prominent in hepatitis C virus (HCV)-negative cases, which was in contrast to our previous reports of significantly increased TSG methylation levels in HCV-positive tumors. Absence of liver cirrhosis and higher FAL scores were identified as independent contributors to significant hypomethylation of rDNA in HCC. Among the chromosomal alterations frequently observed in HCC, loss of 8p, which was unique in the earliest stages of hepatocarcinogenesis, was significantly associated with hypomethylation of rDNA by multivariable analysis (p=0.0153). rDNA hypomethylation was also associated with a high FAL score regardless of tumor differentiation (p=0.0011, well-differentiated; p=0.0089, moderately/poorly-differentiated HCCs). We conclude that DNA hypomethylation is an important cause of CIN in the earliest step of HCC, especially in a background of non-cirrhotic liver.
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-sayama, Japan ; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Nishida
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nishimura
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Arizumi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitai
authors.forename: Norihisa
authors.initials: N
authors.lastname: Yada
authors.forename: Satoru
authors.initials: S
authors.lastname: Hagiwara
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Inoue
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Minami
authors.forename: Kazuomi
authors.initials: K
authors.lastname: Ueshima
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Sakurai
authors.forename: Naosuke
authors.initials: N
authors.lastname: Yokomichi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology* / Q000235:genetics*; D002869:Chromosome Aberrations; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged
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