Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas
Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas
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DOI：
10.1093/carcin/bgn170
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发表时间：
2008-10-01
期刊：
影响因子：
4.7
通讯作者：
Sekido, Yoshitaka
中科院分区：
文献类型：
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作者：
Gao, Wentao;Kondo, Yutaka;Sekido, Yoshitaka
肝细胞癌（HCC）最常见的原因是由于遗传和表观遗传异常引起的病毒感染引起的慢性炎症。目前对HCC的表观遗传变化还缺乏全面的了解。我们使用甲基化CpG岛扩增微阵列（MCAMs）研究了HCC和邻近肿瘤前组织[慢性肝炎（CH）或肝硬化（LC）]中的6458个CpG岛，并与未存在病毒感染和肝炎的正常肝组织进行了比较。MCAM在hcc中鉴定出719个（11%）突出的高甲基化基因。LC引起的hcc甲基化程度明显高于CH（1249个基因（19%）比444个基因（7%），P < 0.05）。有四种异常甲基化模式：I型（4%，如基质金属蛋白酶14）在邻近组织中显示出相当高的甲基化水平，在癌症中不会进一步增加。II型（55%，如RASSF1A）显示从邻近组织到HCC的甲基化逐渐增加。III型（4%，如GNA14）在邻近组织中甲基化减少，但在HCC中甲基化相似或增加。IV型（37%，如CDKN2A）在正常组织和邻近组织中甲基化水平较低，但在HCC中甲基化水平较高。这些DNA甲基化变化通过定量焦磷酸测序甲基化分析证实了24个代表性基因，并分析了38例患者的临床病理参数的相关性。有趣的是，IV型基因的甲基化是中度/低分化癌症的特征。我们的全球表观基因组分析揭示了不同的甲基化模式，可能代表hcc中不同的病理生理过程。
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.