Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis
Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis
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DOI：
10.1016/s0002-9440(10)63495-5
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发表时间：
2003-10-01
影响因子：
6
通讯作者：
Kang, GH
中科院分区：
文献类型：
--
作者：
Lee, S;Lee, HJ;Kang, GH
为探讨多步肝癌发生过程中多个肿瘤相关基因的甲基化状态，采用甲基化特异性聚合酶链反应（methylation-specific polymerase chain reaction，PCR）技术检测了60例肝癌（HCC）和非肝癌（non-HCC）肝组织、22例异型增生结节（dysplastic nodule，DN）、30例肝硬化（liver cirrhosis，LC）、34例慢性肝炎（chronic hepatitis，CH）和20例正常肝组织中9个基因的CpG岛甲基化状态。9个基因的甲基化状态与肝癌患者的临床病理特征相关。所有HCC标本均存在至少一个基因的甲基化，而DN和LC中分别有72.7%和40%存在甲基化，而CH和正常肝组织中均未发现甲基化（P < 0.001）。随着临床分期的进展，甲基化基因数逐步增加（正常肝和CH为0，LC为0.5，DN为1.5，HCC为3.7（P < 0.001））。肝癌组织中甲基化频率较高的基因依次为APC（81.7%）、GSTP 1（76.7%）、RASSF 1A（66.7%）、p16（48.3%）、考克斯-2 III和E-cadherin（33.3%）。在无并发HCC的LC和CH患者中，考克斯-2、p16、RASSF 1A和TIMP-3均未甲基化。慢性肝病合并HCC患者的基因甲基化频率较高，甲基化基因的数量也高于未合并HCC的患者。有E-cadherin或GSTP 1甲基化的HCC患者的生存率低于无甲基化的患者（P分别为0.034和0.043）。总之，我们的研究结果表明，CpG岛甲基化的肿瘤相关基因是一个早期和频繁的事件，并逐步积累在多步骤的肝癌发生。E-cadherin和GSTP 1的CpG岛甲基化可作为HCC患者预后的潜在生物标志物。
To determine the methylation profile of multiple tumor-related genes during multistep hepatocarcinogenesis, we investigated the methylation status of CpG islands of 9 genes, using methylation-specific polymerase chain reaction for 60 paired hepatocellular carcinoma (HCC) and non-HCC liver tissue samples, 22 dysplastic nodule (DN), 30 liver cirrhosis (LC), 34 chronic hepatitis (CH) and 20 normal liver samples. The methylation status of 9 genes was correlated to the clinicopathological findings of HCC patients. All HCC samples showed methylation of at least one gene, whereas it was shown in 72.7% of DN and 40% of LC, but was not shown in CH and normal liver samples (P < 0.001). The number of genes methylated showed a stepwise increase with the progression of stages (0 for normal liver and CH, 0.5 for LC, 1.5 for DN, and 3.7 for HCC (P < 0.001)). The genes frequently methylated in HCC were APC (81.7%), GSTP1 (76.7%), RASSF1A (66.7%), p16 (48.3%), COX-2 ill and E-cadherin (33.3%). COX-2, p16, RASSF1A, and TIMP-3 were not methylated in LC and CH from patients without concurrent HCC. Chronic liver diseases with concurrent HCC showed higher methylation frequencies of the tested genes, and a higher number of methylated genes than those without concurrent HCC. HCC patients with methylation of E-cadherin or GSTP1 showed poorer survival than those without (P = 0.034 and 0.043, respectively). In conclusion, our results indicated that CpG island methylation of tumor-related genes is an early and frequent event, and accumulates step-by-step during a multistep hepatocarcinogenesis. CpG island methylation of E-cadherin or GSTP1 might serve as a potential biomarker for prognostication of HCC patients.