Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets
Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets
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DOI：
10.1002/hep.21467
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发表时间：
2007-01-01
期刊：
影响因子：
13.5
通讯作者：
Zucman-Rossi, Jessica
中科院分区：
文献类型：
--
作者：
Boyault, Sandrine;Rickman, David S.;Zucman-Rossi, Jessica
肝细胞癌是一组不同的肿瘤，其危险因素和基因改变各不相同。我们进一步研究了转录组-基因-表型在肝细胞癌中的相关性。对57例肝细胞癌和3例肝细胞腺瘤进行了整体转录组学分析，并用另外63例肝细胞癌进行了定量RT-PCR验证。我们测定了每个肿瘤的杂合性丢失、基因突变、CDH1和CDKN2A启动子甲基化以及HBVDNA拷贝数。非监督转录组分析确定了6个与临床和遗传特征相关的肝癌亚群(G1-G6)。G1期肿瘤与低拷贝数的乙肝病毒和高表达的基因在胎肝中表达有关，并受双亲印迹控制。G2包括感染高拷贝数的乙肝病毒和PIK3C4和TP53突变的肝癌细胞。在第一组中，我们检测到AKT通路的特异性激活。G3肿瘤以TP53突变和控制细胞周期的基因过度表达为典型。G4是一个异质性肿瘤亚群，包括TCF1突变的肝细胞腺瘤和癌。G5和G6与导致Wnt途径激活的β-catenin突变密切相关；特别是G6肿瘤的特点是卫星结节，Wnt途径激活程度高，E-钙粘蛋白表达低。结论：这些结果加深了我们对人肝细胞癌遗传多样性的认识，并为肿瘤的分类提供了特异的标志物。此外，我们的分类具有潜在的治疗意义，因为50%的肿瘤与WNT或AKT通路激活有关，这可能是特定抑制治疗的靶点。
Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. We further investigated transcriptome-genotype-phenotype correlations in HCC. Global transcriptome analyses were performed on 57 HCCs and 3 hepatocellular adenomas and validated by quantitative RT-PCR using 63 additional HCCs. We determined loss of heterozygosity, gene mutations, promoter methylation of CDH1 and CDKN2A, and HBV DNA copy number for each tumor. Unsupervised transcriptome analysis identified 6 robust subgroups of HCC (G1-G6) associated with clinical and genetic characteristics. G1 tumors were associated with low copy number of HBV and overexpression of genes expressed in fetal liver and controlled by parental imprinting. G2 included HCCs infected with a high copy number of HBV and mutations in PIK3C4 and TP53. In these first groups, we detected specific activation of the AKT pathway. G3 tumors were typified by mutation of TP53 and overexpression of genes controlling the cell cycle. G4 was a heterogeneous subgroup of tumors including TCF1-mutated hepatocellular adenomas and carcinomas. G5 and G6 were strongly related to beta-catenin mutations that lead to Wnt pathway activation; in particular, G6 tumors were characterized by satellite nodules, higher activation of the Wnt pathway, and E-cadherin underexpression. Conclusion: These results have furthered our understanding of the genetic diversity of human HCC and have provided specific identifiers for classifying tumors. In addition, our classification has potential therapeutic implications because 50% of the tumors were related to WNT or AKT pathway activation, which potentially could be targeted by specific inhibiting therapies.