Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes.
Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes.
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DOI：
10.1053/j.gastro.2013.01.001
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发表时间：
2013-04
期刊：
影响因子：
29.4
通讯作者：
Llovet JM
中科院分区：
文献类型：
--
作者：
Sia D;Hoshida Y;Villanueva A;Roayaie S;Ferrer J;Tabak B;Peix J;Sole M;Tovar V;Alsinet C;Cornella H;Klotzle B;Fan JB;Cotsoglou C;Thung SN;Fuster J;Waxman S;Garcia-Valdecasas JC;Bruix J;Schwartz ME;Beroukhim R;Mazzaferro V;Llovet JM
胆管癌是第二常见的肝癌，可分为肝内胆管癌（ICC）或肝外胆管癌。我们对来自大量患者的ICC样本进行了综合基因组分析。我们使用福尔马林固定的149例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。研究了119例患者的临床病理特征和患者结局之间的关系。类别发现基于非负矩阵因子分解算法，并通过GISTIC分析鉴定显著的拷贝数变异。基因集富集分析用于鉴定在特定分子类别的肿瘤中激活的信号传导通路，并分析其与肝细胞癌（HCC）的基因组重叠。我们确定了ICC的2个主要生物学类别。炎症类别（38%的ICC）的特征在于炎症信号通路的激活、细胞因子的过表达和STAT 3激活。增殖类（62%）的特征是致癌信号通路（包括RAS、丝裂原活化蛋白激酶和MET）的激活、11q13.2处的DNA扩增、14q22.1处的缺失、KRAS和BRAF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组。我们在5个区域发现了高水平的扩增，包括1 p13（9%）和11q13.2（4%），以及几个局灶性缺失，如9p21.3（18%）和14q22.1（12%）在SAV 1肿瘤抑制基因的编码区。在一个互补的方法中，我们确定了一个基因表达特征，与ICC患者的生存时间减少有关;这个特征在增殖类中富集（P <0.001）。我们使用综合基因组分析来鉴定2类ICC。增殖类型具有特定的拷贝数改变，这是HCC预后不良特征的许多特征，并且与预后不良相关。因此，基于分子特征的不同类型的ICC可能需要不同的治疗方法。
Cholangiocarcinoma, the second most common liver cancer, can be classified as intra-hepatic 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 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, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches.
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影响因子：
11.2
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
通讯作者：
Golub TR
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
29.4
作者：
Isomoto, Hajime;Mott, Justin L.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
13.5
作者：
Jinawath, Natini;Chamgramol, Yaovalux;Nakamura, Yusuke
通讯作者：
Nakamura, Yusuke
胆管癌：发病机理，诊断和治疗的进展。
影响因子：
13.5
作者：
Blechacz, Boris;Gores, Gregory J.
通讯作者：
Gores, Gregory J.