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[多种基因的异常甲基化及其在肝细胞癌中的临床意义]

[Aberrant methylation of multiple genes and its clinical implication in hepatocellular carcinoma].

作者信息

Lou Cheng, Yang Bin, Gao Ying-tang, Wang Yi-jun, Nie Fu-hua, Yuan Qiang, Zhang Chun-li, Du Zhi

机构信息

Department of Hepatobiliary Surgery, The Third Central Hospital, Tianjin Medical University, Tianjin 300170, China.

出版信息

Zhonghua Zhong Liu Za Zhi. 2008 Nov;30(11):831-6.

PMID:19173828

Abstract

OBJECTIVE

To investigate the methylation frequencies of multiple tumor suppressor genes (TSGs) in hepatocellular carcinoma (HCC) and the clinical implication of aberrant DNA methylation in molecular carcinogenesis of HCC.

METHODS

Sixty samples of HCC and the paired adjacent liver tissue, 16 samples from post-hepatitis cirrhotic livers, 5 from livers with chronic hepatitis and 5 from normal livers were collected. Eight TSGs frequently silenced by hypermethylation of their promoters in various types of digestive tumors were selected, including APC, RASSF1A, p16, GSTP1, MGMT, DAPK, SOCS-1 and RIZ1. The status of promoter methylation in these 8 genes was investigated using methylation-specific polymerase chain reaction. The clinicopathological data of HCC were also analyzed in order to evaluate the clinical implication of aberrant methylation in HCC.

RESULTS

Methylation of the 8 TSGs was quite frequent in HCC, with a methylation rate of 95.0% in RASSF1A, 90.0% in APC, 73.3% in GSTP1, 65.0% in p16, 61.6% in RIZ1 and 60.0% in MGMT. Methylation of the 6 genes was more frequent in HCC than that in adjacent tissues (P < 0.05). The methylation rate of MGMT, GSTP1 and RIZ1 in the adjacent tissues was 41.6%, 40.0% and 25.0%, respectively, significantly higher than that in cirrhotic liver (P < 0.05). p16 methylation was more frequently observed in HCC in elderly patients. The frequency of MGMT methylation was tended to be higher in giant HCC than that in the other types of HCC. Patients with MGMT methylation in the tumor were found to have a shorter disease free survival.

CONCLUSION

Different frequency of methylation in hepatocellular carcinomas, adjacent liver tissues and cirrhotic livers implies that epigenetic alteration in the hepatocellular carcinogenesis may be a gradually progressive process. Methylation status of MGMT, GSTP1 and RIZ1 may be promising in risk assessment of hepatocellular carcinoma and in early diagnosis. Furthermore, MGMT methylation might be also used as a potential prognostic biomarker for hepatocellular carcinoma patients.

摘要

目的

探讨肝细胞癌（HCC）中多个肿瘤抑制基因（TSGs）的甲基化频率以及异常DNA甲基化在HCC分子致癌过程中的临床意义。

方法

收集60例HCC样本及其配对的癌旁肝组织、16例肝炎后肝硬化肝组织、5例慢性肝炎肝组织和5例正常肝组织。选择8个在各种类型消化肿瘤中因启动子高甲基化而频繁沉默的TSGs，包括APC、RASSF1A、p16、GSTP1、MGMT、DAPK、SOCS-1和RIZ1。采用甲基化特异性聚合酶链反应研究这8个基因启动子的甲基化状态。同时分析HCC的临床病理数据，以评估异常甲基化在HCC中的临床意义。

结果

8个TSGs在HCC中甲基化相当频繁，RASSF1A甲基化率为95.0%，APC为90.0%，GSTP1为73.3%，p16为65.0%，RIZ1为61.6%，MGMT为60.0%。6个基因在HCC中的甲基化频率高于癌旁组织（P<0.05）。MGMT、GSTP1和RIZ1在癌旁组织中的甲基化率分别为41.6%、40.0%和25.0%，显著高于肝硬化肝组织（P<0.05）。老年HCC患者中p16甲基化更为常见。巨块型HCC中MGMT甲基化频率倾向于高于其他类型HCC。肿瘤中MGMT甲基化的患者无病生存期较短。