Genome-wide analysis of DNA methylation identifies novel cancer-related genes in hepatocellular carcinoma
Genome-wide analysis of DNA methylation identifies novel cancer-related genes in hepatocellular carcinoma
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DOI：
10.1007/s13277-012-0378-3
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发表时间：
2012-03
期刊：
影响因子：
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通讯作者：
M. Shitani;S. Sasaki;N. Akutsu;H. Takagi;Hiromu Suzuki;M. Nojima;Hiroyuki Yamamoto;T. Tokino
中科院分区：
文献类型：
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作者：
M. Shitani;S. Sasaki;N. Akutsu;H. Takagi;Hiromu Suzuki;M. Nojima;Hiroyuki Yamamoto;T. Tokino
DNA甲基化异常与肝细胞癌（HCC）的发生有关。我们的目的是阐明其分子机制，并确定有用的生物标志物，通过筛选DNA甲基化在肝癌。甲基化CpG岛扩增结合CpG岛微阵列（MCAM）分析用于筛查原发性HCC标本中的甲基化基因[B肝炎病毒（HBV）阳性，n= 4;丙型肝炎病毒（HCV）阳性，n= 5; HBV/HCV阴性，n= 7]。亚硫酸氢盐焦磷酸测序用于分析来自HCC患者的HCC组织（n= 57）和非癌肝组织（n = 50）以及HCC细胞系（n= 10）中所选基因和长散布核元件（LINE）-1的甲基化。MCAM分析在HBV阳性、HCV阳性和HBV/HCV阴性HCC组织中分别鉴定出332、342和259个甲基化基因。在这些基因中，KLHL 35、PAX 5、PENK和SPDYA的甲基化在HCC组织中显著高于非癌肝组织，与肝炎病毒状态无关。LINE-1低甲基化在HCC中也普遍存在，并与KLHL 35和SPDYA甲基化呈正相关。受试者工作特征曲线分析显示，四个基因和LINE-1的甲基化在HCC组织和非癌肝组织中具有很强的区分性。我们的数据表明，异常的高甲基化和低甲基化可能有助于肝癌的共同发病机制。KLHL 35、PAX、PENK和SDPYA的高甲基化和LINE-1的低甲基化可能是检测HCC的有用生物标志物。
Aberrant DNA methylation has been implicated in the development of hepatocellular carcinoma (HCC). Our aim was to clarify its molecular mechanism and to identify useful biomarkers by screening for DNA methylation in HCC. Methylated CpG island amplification coupled with CpG island microarray (MCAM) analysis was carried out to screen for methylated genes in primary HCC specimens [hepatitis B virus (HBV)-positive,n= 4; hepatitis C virus (HCV)-positive,n= 5; HBV/HCV-negative,n= 7]. Bisulfite pyrosequencing was used to analyze the methylation of selected genes and long interspersed nuclear element (LINE)-1 in HCC tissue (n= 57) and noncancerous liver tissue (n= 50) from HCC patients and in HCC cell lines (n= 10). MCAM analysis identified 332, 342, and 259 genes that were methylated in HBV-positive, HCV-positive, and HBV/HCV-negative HCC tissues, respectively. Among these genes, methylation ofKLHL35,PAX5,PENK, andSPDYAwas significantly higher in HCC tissue than in noncancerous liver tissue, irrespective of the hepatitis virus status. LINE-1 hypomethylation was also prevalent in HCC and correlated positively withKLHL35andSPDYAmethylation. Receiver operating characteristic curve analysis revealed that methylation of the four genes and LINE-1 strongly discriminated between HCC tissue and noncancerous liver tissue. Our data suggest that aberrant hyper- and hypomethylation may contribute to a common pathogenesis mechanism in HCC. Hypermethylation ofKLHL35,PAX,PENK, andSDPYAand hypomethylation of LINE-1 could be useful biomarkers for the detection of HCC.