Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling
Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling
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DOI：
10.1002/hep.20878
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发表时间：
2005-10-01
期刊：
影响因子：
13.5
通讯作者：
Lee, JY
中科院分区：
文献类型：
--
作者：
Nam, SW;Park, JY;Lee, JY
肝细胞癌（HCC）的进展是一个逐步的过程，从癌前病变-包括低度异型增生结节（LGDNs）和高度异型增生结节（HGDNs）-进展到晚期HCC。然而，与这种进展相关的分子变化尚不清楚，并且认为区分肿瘤前病变和高分化HCC的形态学线索并没有被普遍接受。为了在分子水平上了解肝癌发生的多步骤过程，我们使用寡核苷酸微阵列研究了50例肝细胞结节性病变的转录谱，范围从LGDNs到原发性HCC（Edmondson 1-3级）。我们证明，基因表达谱不仅可以区分异型增生结节和显性癌，而且可以通过10，376个基因的无监督分层聚类来区分HCC的不同组织学分级。我们确定了3,084个与肿瘤进展相关的等级相关基因，使用单因素方差分析和一个对所有未合并的t检验。这些基因的功能分配揭示了离散的表达簇，代表肝癌的分级依赖性生物学特性。使用对角线性判别分析和支持向量机，我们确定了240个可以根据组织学分级准确分类肿瘤的基因，特别是当试图区分LGDN，HGDN和I级HCC时。总之，在异型增生结节和显性HCC之间存在明确的分子界限。从I级到3级HCC的进展与基因表达的变化相关，与合理的功能结果一致。
Progression of hepatocellular carcinoma (HCC) is a stepwise process that proceeds from preneoplastic lesions-including low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs)-to advanced HCC. The molecular changes associated with this progression are unclear, however, and the morphological cues thought to distinguish pre-neoplastic lesions from well-differentiated HCC are not universally accepted. To understand the multistep process of hepato-carcinogenesis at the molecular level, we used oligo-nucleotide microarrays to investigate the transcription profiles of 50 hepatocellular nodular lesions ranging from LGDNs to primary HCC (Edmondson grades 1-3). We demonstrated that gene expression profiles can discriminate not only between dysplastic nodules and overt carcinoma but also between different histological grades of HCC via unsupervised hierarchical clustering with 10,376 genes. We identified 3,084 grade-associated genes, correlated with tumor progression, using one-way ANOVA and a one-versus-all unpooled t test. Functional assignment of these genes revealed discrete expression clusters representing grade-dependent biological properties of HCC. Using both diagonal linear discriminant analysis and support vector machines) we identified 240 genes that could accurately classify tumors according to histological grade, especially when attempting to discriminate LGDNs, HGDNs, and grade I HCC. In conclusion, a dear molecular demarcation between dysplastic nodules and overt HCC exists. The progression from grade I through grade 3 HCC is associated with changes in gene expression consistent with plausible functional consequences.