Identification of genes preferentially methylated in hepatitis C virus-related hepatocellular carcinoma
Identification of genes preferentially methylated in hepatitis C virus-related hepatocellular carcinoma
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DOI：
10.1111/j.1349-7006.2010.01549.x
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发表时间：
2010-06-01
期刊：
影响因子：
5.7
通讯作者：
Kaneda, Atsushi
中科院分区：
文献类型：
--
作者：
Deng, Ying-Bing;Nagae, Genta;Kaneda, Atsushi
B肝炎病毒（HBV）和丙型肝炎病毒（HCV）的慢性感染似乎是肝细胞癌（HCC）的最重要原因。已知异常启动子甲基化与癌症（包括HCC）密切相关。在这项研究中，我们分析了异常启动子甲基化的甲基化DNA免疫沉淀芯片分析在全基因组范围内的六个肝癌，包括三个HBV相关和三个HCV相关的肝癌，六个匹配的非癌肝组织，和三个正常肝组织。启动子甲基化的候选基因在HCV相关的HCC中更常见。检测并选择优先甲基化HBV相关或HCV相关HCC的候选基因，并使用MALDI-TOF质谱法通过定量甲基化分析验证所选基因的甲基化水平，使用125个肝组织样本，包括61个HCC（28个HBV相关HCC和33个HCV相关HCC）和59个匹配的非癌肝脏，以及5个正常肝脏。在分析的基因中，HBV相关HCC中的优先甲基化仅在一个基因中得到验证。然而，15个基因被发现在HCV相关的HCC中优先甲基化，这与年龄无关。使用这些基因的HCC的分层聚类将HCV相关HCC分层为频繁甲基化样品的聚类。这15个基因包括抑制癌症相关信号传导的基因，如RAS/RAF/ERK和Wnt/β-连环蛋白途径。双特异性磷酸酶4（DUSP 4）、细胞色素P450、家族24、亚家族A、多肽1（CYP 24 A1）和利钠肽受体A（NPR 1）的甲基化与无复发生存率显著相关。结果表明，HCV相关HCC中存在优先甲基化的基因，DNA甲基化可能通过沉默癌相关通路抑制因子在HCV相关HCC中发挥重要作用，并可能作为一种预后指标。（Cancer Sci 2010）。
Chronic infections by hepatitis B virus (HBV) and hepatitis C virus (HCV) appear to be the most significant causes of hepatocellular carcinoma (HCC). Aberrant promoter methylation is known to be deeply involved in cancer, including in HCC. In this study, we analyzed aberrant promoter methylation by methylated DNA immunoprecipitation-on-chip analysis on a genome-wide scale in six HCCs including three HBV-related and three HCV-related HCCs, six matched noncancerous liver tissues, and three normal liver tissues. Candidate genes with promoter methylation were detected more frequently in HCV-related HCC. Candidate genes methylated preferentially to HBV-related or HCV-related HCCs were detected and selected, and methylation levels of the selected genes were validated by quantitative methylation analysis using MALDI-TOF mass spectrometry using 125 liver tissue samples, including 61 HCCs (28 HBV-related HCCs and 33 HCV-related HCCs) and 59 matched noncancerous livers, and five normal livers. Among analyzed genes, preferential methylation in HBV-related HCC was validated in one gene only. However, 15 genes were found to be methylated preferentially in HCV-related HCC, which was independent from age. Hierarchical clustering of HCC using these genes stratified HCV-related HCC as a cluster of frequently methylated samples. The 15 genes included genes inhibitory to cancer-related signaling such as RAS/RAF/ERK and Wnt/beta-catenin pathways. Methylation of dual specificity phosphatase 4 (DUSP4), cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), and natriuretic peptide receptor A (NPR1) significantly correlated with recurrence-free survival. It was indicated that genes methylated preferentially in HCV-related HCC exist, and that DNA methylation might play an important role in HCV-related HCC by silencing cancer-related pathway inhibitors, and might perhaps be useful as a prognostic marker. (Cancer Sci 2010).