Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.
Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.
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DOI：
10.1158/0008-5472.can-09-1089
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发表时间：
2009-09-15
期刊：
影响因子：
11.2
通讯作者：
Golub TR
中科院分区：
文献类型：
--
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
肝细胞癌（HCC）是一种高度异质性的疾病，先前开发基于基因组学的肝细胞癌分类的尝试产生了差异很大的结果，表明难以确定统一的分子特征。我们对来自全球8个独立患者队列的数据集中的基因表达谱进行了荟萃分析。此外，为了确定分类系统在现实世界中的适用性，我们对来自另外一个患者队列的118个福尔马林固定、石蜡包埋的组织进行了分析。共分析了603名患者，涵盖了从西方国家和东方国家收集的肝细胞癌的主要病因（乙型和丙型肝炎）。我们观察到3种稳健的肝细胞癌亚类（分别称为S1、S2和S3），每种亚类都与临床参数相关，如肿瘤大小、细胞分化程度和血清甲胎蛋白水平。对特征组成的分析表明，S1反映了WNT信号通路的异常激活，S2的特征是增殖以及MYC和AKT激活，S3与肝细胞分化相关。功能研究表明，S1肿瘤所特有的WNT通路激活特征并非仅仅是β-连环蛋白突变的结果，而是转化生长因子-β激活的结果，因此代表了肝细胞癌中WNT通路激活的一种新机制。这些实验建立了首个基于基因表达谱的肝细胞癌共识分类框架，并凸显了整合多个数据集以确定该疾病稳健的分子分类的能力。
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomics-based classification for HCC have yielded highly divergent results, indicating difficulty to identify unified molecular anatomy. We performed a meta-analysis of gene expression profiles in datasets from 8 independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed 3 robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of beta-catenin mutation, but rather was the result of TGF-beta activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene-expression profiles, and highlight the power of integrating of multiple datasets to define a robust molecular taxonomy of the disease.