Barcelona-Clínic Liver Cancer Group (HCC Translational Research Laboratory, Liver Unit, Pathology Department), Institut d'Investigacions Biomèdiques August Pi I Sunyer, Liver Unit, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain.
Gastroenterology. 2013 Apr;144(4):829-40. doi: 10.1053/j.gastro.2013.01.001. Epub 2013 Jan 4.
BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients.
We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC).
We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation-based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P < .001).
We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches.
胆管癌是第二大常见肝癌，可分为肝内胆管癌（ICC）或肝外胆管癌。我们对一大系列 ICC 患者的样本进行了综合基因组分析。
我们对 149 例患者的福尔马林固定 ICC 样本进行了基因表达谱、高密度单核苷酸多态性阵列和突变分析。对 119 例病例进行了与临床病理特征和患者预后的关联分析。分类发现基于非负矩阵分解算法，通过癌症基因组鉴定显著靶点（GISTIC）分析鉴定显著的拷贝数变化。基因集富集分析用于鉴定肿瘤特定分子类型中激活的信号通路，并分析其与肝细胞癌（HCC）的基因组重叠。
我们鉴定了 2 种主要的 ICC 生物学类型。炎症类（38%的 ICC）的特点是炎症信号通路的激活、细胞因子的过表达和 STAT3 的激活。增殖类（62%）的特点是致癌信号通路的激活（包括 RAS、丝裂原激活蛋白激酶和 MET）、11q13.2 的 DNA 扩增、14q22.1 的缺失、KRAS 和 BRAF 的突变以及先前与 HCC 患者预后不良相关的基因表达特征。基于拷贝数变异的聚类能够进一步细化这些分子群。我们鉴定了 5 个区域的高水平扩增，包括 1p13（9%）和 11q13.2（4%），以及几个局灶性缺失，如 9p21.3（18%）和 14q22.1（编码区 SAV1 肿瘤抑制因子的 12%）。在一种补充方法中，我们鉴定了一个与 ICC 患者生存时间缩短相关的基因表达特征；该特征在增殖类中富集（P <.001）。
我们使用综合基因组分析鉴定了 2 种 ICC 类型。增殖类具有特定的拷贝数改变、致癌途径的激活，并与不良预后相关。基于分子特征的不同 ICC 类型可能需要不同的治疗方法。
