Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.
Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.
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DOI：
10.1371/journal.pone.0115383
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Javle M
中科院分区：
文献类型：
--
作者：
Churi CR;Shroff R;Wang Y;Rashid A;Kang HC;Weatherly J;Zuo M;Zinner R;Hong D;Meric-Bernstam F;Janku F;Crane CH;Mishra L;Vauthey JN;Wolff RA;Mills G;Javle M
胆管细胞癌(CCA)具有异质性，肝内外胆管细胞癌的临床表现多种多样。下一代测序(NGS)技术可以识别这些实体之间的遗传差异，并识别靶向治疗的分子亚群。我们描述了75例CCA患者成功的基于NGS的检测，以及结果的预后和治疗意义。使用Ion PGM Sequencer上的318芯片的46个癌症相关基因的热点区域的NGS面板或b)Illumina HiSeq 2000测序平台对236个癌症相关基因的3,769个外显子加上19个基因的47个内含子进行突变分析，平均深度为1000倍。临床数据被提取并与临床结果相关联。有靶向突变的患者被转介到适当的临床试验。肝内组(n = 55)和肝外组(n = 2 0)在遗传变异(GAS)的性质和频率上存在显著差异。肝内CCA组IDH1和DNA修复基因改变较多见，而肝外组较多见ERBB2 GAS。肝内CCA中常见的GAS依次为TP53(35%)、KRAS(24%)、ARID1A(20%)、IDH1(18%)、MCL1(16%)和PBRM1(11%)。肝外CCA(n = 2 0)最常见的GAS依次为TP5 3(45%)、KRAS(40%)、ERBB2(2 5%)、Smad4(2 5%)、FBXW7(15%)和CDKN2 A(15%)。在肝内CCA中，KRAS、TP53或MAPK/mTOR气体与预后显著相关，而FGFR气体与相对无痛病程相关。IDH1气体对预后无任何意义。染色质调节基因BAP1和PBRM1中的GAS与肝外CCA的骨转移和生存不良有关。EGFR、FGFR、C-MET、B-RAF和MEK抑制剂的放射学反应和临床益处显著。肝内和肝外CCA之间存在显著的遗传差异。NGS可以潜在地识别具有不同预后和治疗意义的疾病亚组。
Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics. We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials. There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors. There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.
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DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
7.5
作者：
Goeppert, Benjamin;Frauenschuh, Lena;Capper, David
通讯作者：
Capper, David
影响因子：
28.2
作者：
Bose R;Kavuri SM;Searleman AC;Shen W;Shen D;Koboldt DC;Monsey J;Goel N;Aronson AB;Li S;Ma CX;Ding L;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ
影响因子：
4.7
作者：
Herter-Sprie GS;Greulich H;Wong KK
通讯作者：
Wong KK