Nishida Naoshi, Nishimura Takafumi, Nakai Takuya, Chishina Hirokazu, Arizumi Tadaaki, Takita Masahiro, Kitai Satoshi, Yada Norihisa, Hagiwara Satoru, Inoue Tatsuo, Minami Yasunori, Ueshima Kazuomi, Sakurai Toshiharu, Kudo Masatoshi
Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
Dig Dis. 2014;32(6):658-63. doi: 10.1159/000367982. Epub 2014 Oct 29.
To clarify the progression pattern of abnormal DNA methylation during the development of hepatocellular carcinoma (HCC) using a comprehensive methylation assay.
We used an Infinium HumanMethylation450 BeadChip array that can analyze >485,000 CpG sites distributed throughout the genome for a comprehensive methylation study of 117 liver tissues consisting of 59 HCC and 58 noncancerous livers. Altered DNA methylation patterns during tumor progression were also analyzed.
We identified 38,330 CpG sites with significant differences in methylation levels between HCCs and noncancerous livers (DM-CpGs) using strict criteria. Of the DM-CpGs, 92% were hypomethylated and only 3,051 CpGs (8%) were hypermethylated in HCC. The DM-CpGs were more prevalent within intergenic regions with isolated CpGs. In contrast, DM-CpGs that were hypermethylated in HCC were predominantly located within promoter regions and CpG islands (p < 0.0001). The association between methylation profiles of DM-CpGs and tumor size was statistically significant, especially in hepatitis C virus (HCV)-positive cases (p = 0.0001).
We clarified the unique characteristics of DM-CpGs in human HCCs. The stepwise progression of alterations in DNA methylation was a common feature of HCV-related hepatocarcinogenesis.
使用全面的甲基化检测方法阐明肝细胞癌（HCC）发生发展过程中异常DNA甲基化的进展模式。
我们使用了Infinium HumanMethylation450 BeadChip芯片，该芯片可分析遍布全基因组的超过485,000个CpG位点，对117个肝脏组织进行全面甲基化研究，其中包括59个HCC组织和58个非癌肝脏组织。还分析了肿瘤进展过程中DNA甲基化模式的变化。
我们使用严格标准鉴定出38,330个在HCC组织和非癌肝脏组织之间甲基化水平存在显著差异的CpG位点（差异甲基化CpG位点，DM-CpGs）。在这些DM-CpGs中，92%在HCC中发生低甲基化，只有3051个CpG位点（8%）发生高甲基化。DM-CpGs在具有孤立CpG的基因间区域更为普遍。相比之下，在HCC中发生高甲基化的DM-CpGs主要位于启动子区域和CpG岛（p < 0.0001）。DM-CpGs的甲基化谱与肿瘤大小之间的关联具有统计学意义（p = 0.0001），在丙型肝炎病毒（HCV）阳性病例中尤为明显。
我们阐明了人类HCC中DM-CpGs的独特特征。DNA甲基化改变的逐步进展是HCV相关肝癌发生的一个共同特征。
