Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma.
Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma.
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DOI：
10.1016/j.jhep.2020.03.008
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发表时间：
2020-08
影响因子：
25.7
通讯作者：
Llovet JM
中科院分区：
文献类型：
--
作者：
Montal R;Sia D;Montironi C;Leow WQ;Esteban-Fabró R;Pinyol R;Torres-Martin M;Bassaganyas L;Moeini A;Peix J;Cabellos L;Maeda M;Villacorta-Martin C;Tabrizian P;Rodriguez-Carunchio L;Castellano G;Sempoux C;Minguez B;Pawlik TM;Labgaa I;Roberts LR;Sole M;Fiel MI;Thung S;Fuster J;Roayaie S;Villanueva A;Schwartz M;Llovet JM
胆管癌（CCA）是一种致命的胆管恶性肿瘤，根据其解剖位置可分为肝内（iCCA）和肝外（eCCA），两者有不同的发病机制和临床处理。对eCCA的分子结构知之甚少，也没有临床有效的靶向治疗被批准。我们的目的是提供eCCA的分子分类，并确定分子治疗的潜在靶点。对189例eCCA病例的国际多中心队列进行了综合基因组分析。基因组分析包括全基因组表达、靶向dna测序和免疫组织化学。在ICGC的181例外部胆道肿瘤中证实了分子发现。KRAS（36.7%）、TP53（34.7%）、ARID1A（14%）和SMAD4（10.7%）是最常见的突变，根据OncoKB，约25%的肿瘤具有假定的可操作的基因组改变。基于转录组的无监督聚类帮助我们定义了eCCA的四个分子类别。代谢类肿瘤（19%）表现为肝细胞样表型，转录因子HNF4A激活，与胆汁酸代谢相关的基因特征富集。增殖类（23%）在远端CCA患者中更常见，其特征是MYC靶点富集、ERBB2突变/扩增和mTOR信号激活。间充质类（47%）由上皮-间充质转化、异常TGF-β信号传导和较差的总生存率来定义。最后，免疫类肿瘤（11%）具有较高的淋巴细胞浸润、PD-1/PD-L1过表达以及与免疫检查点抑制剂更好应答相关的分子特征。综合分子表征确定了不同亚类的eCCA。每一类的基因组特征为探索患者分层和新的治疗方法提供了基本原理。靶向治疗尚未被批准用于肝外胆管癌的治疗。我们在189名患者中对该肿瘤进行了多平台分子表征。这些分析揭示了四种新的基于转录组的肝外胆管癌分子类别，并鉴定出约25%的肿瘤具有可操作的基因组改变，这具有潜在的预后和治疗意义。
Cholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified on the basis of its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is marginal understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies. An integrative genomic analysis of an international multi-center cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from ICGC. KRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ~25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define four molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations / amplifications and mTOR signaling activation. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGF-β signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors. An integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches. Targeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed four novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ~25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.
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影响因子：
64.8
作者：
Hyman DM;Piha-Paul SA;Won H;Rodon J;Saura C;Shapiro GI;Juric D;Quinn DI;Moreno V;Doger B;Mayer IA;Boni V;Calvo E;Loi S;Lockhart AC;Erinjeri JP;Scaltriti M;Ulaner GA;Patel J;Tang J;Beer H;Selcuklu SD;Hanrahan AJ;Bouvier N;Melcer M;Murali R;Schram AM;Smyth LM;Jhaveri K;Li BT;Drilon A;Harding JJ;Iyer G;Taylor BS;Berger MF;Cutler RE Jr;Xu F;Butturini A;Eli LD;Mann G;Farrell C;Lalani AS;Bryce RP;Arteaga CL;Meric-Bernstam F;Baselga J;Solit DB
通讯作者：
Solit DB
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
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：
29.4
作者：
Ilyas SI;Gores GJ
通讯作者：
Gores GJ
DOI：
10.1158/1078-0432.ccr-16-2363
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Britten CD;Garrett-Mayer E;Chin SH;Shirai K;Ogretmen B;Bentz TA;Brisendine A;Anderton K;Cusack SL;Maines LW;Zhuang Y;Smith CD;Thomas MB
通讯作者：
Thomas MB