Distinct methylation patterns of benign and malignant liver tumors revealed by quantitative methylation profiling
Distinct methylation patterns of benign and malignant liver tumors revealed by quantitative methylation profiling
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DOI：
10.1158/1078-0432.ccr-04-2462
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发表时间：
2005-05-15
影响因子：
11.5
通讯作者：
Flemming, P
中科院分区：
文献类型：
--
作者：
Lehmann, U;Berg-Ribbe, I;Flemming, P
目的：建立了肝细胞癌和最常见的良性肝肿瘤肝细胞腺瘤的比较定量甲基化谱，用于鉴定肿瘤特异性甲基化模式。9个基因的甲基化水平检测41例肝癌组织及癌旁正常肝组织中RASSF 1A、cyclinD 2、p16 INK 4a、DAP-K、APC、RIZ-1、HIN-1、GSTπ 1、SOCS-1的表达，肝细胞腺瘤和邻近正常组织（n = 26）、局灶性结节性增生（n = 10）和无关正常肝组织（n = 28）。累积的甲基化数据进行了分析，使用各种统计算法，包括分层聚类，检测肿瘤特异性甲基化patterns.Results：聚类分析显示，肝细胞腺瘤显示的甲基化谱更相似，发现在正常肝组织和局灶性结节增生比发现在肝细胞癌。许多特征性的差异没有检测到时，使用单纯的定性甲基化测定。细胞周期蛋白D2基因被确定为肝细胞癌异常高甲基化的新且常见的靶点（68%）。在对照组的28例肝标本从健康的捐助者，患者的年龄和频率和异常甲基化的水平之间存在明显的相关性，这不能在组中检测到的肝细胞癌specimens.Conclusions：甲基化分析可以明确地有助于可疑病变的明确分类，但只有在定量的方式应用细胞类型和基因特异性阈值。在肝细胞癌中，伴随恶性转化的甲基化模式改变覆盖了基因甲基化的年龄依赖性增加。
Purpose: A comparative quantitative methylation profiling of hepatocellular carcinoma and the most frequent benign liver tumor, hepatocellular adenoma, was set up for the identification of tumor-specific methylation patterns.Experimental Design: The quantitative methylation levels of nine genes (RASSF1A, cyclinD2, p16INK4a, DAP-K, APC, RIZ-1, HIN-1, GSTπ 1, SOCS-1) were analyzed in hepatocellular carcinoma and adjacent normal tissue (n = 41), hepatocellular adenoma and adjacent normal tissue (n = 26), focal nodular hyperplasia (n = 10), and unrelated normal liver tissue (n = 28). Accumulated methylation data were analyzed using various statistical algorithms, including hierarchical clustering, to detect tumor-specific methylation patterns.Results: Cluster analysis revealed that hepatocellular adenoma displays a methylation profile much more similar to that found in normal liver tissue and focal nodular hyperplasia than to that found in hepatocellular carcinoma. Many characteristic differences were not detected when using mere qualitative methylation assays. The cyclinD2 gene was identified as a new and frequent target for aberrant hypermethylation in hepatocellular carcinoma (68%). In the control group of 28 liver specimens from healthy donors, a clear correlation between age of patient and frequency and level of aberrant methylation was seen, which could not be detected in the group of hepatocellular carcinoma specimens.Conclusions: Methylation profiling can clearly contribute to the unequivocal classification of suspicious lesions, but only if done in a quantitative manner applying cell type and gene-specific thresholds. In hepatocellular carcinoma, the altered methylation patterns accompanying malignant transformation override the age-dependent increase in gene methylation.