Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.
Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.
复制标题
DOI：
10.1016/j.celrep.2017.02.033
复制
发表时间：
2017-03-14
期刊：
影响因子：
8.8
通讯作者：
Kwong LN
中科院分区：
文献类型：
--
作者：
Farshidfar F;Zheng S;Gingras MC;Newton Y;Shih J;Robertson AG;Hinoue T;Hoadley KA;Gibb EA;Roszik J;Covington KR;Wu CC;Shinbrot E;Stransky N;Hegde A;Yang JD;Reznik E;Sadeghi S;Pedamallu CS;Ojesina AI;Hess JM;Auman JT;Rhie SK;Bowlby R;Borad MJ;Cancer Genome Atlas Network;Zhu AX;Stuart JM;Sander C;Akbani R;Cherniack AD;Deshpande V;Mounajjed T;Foo WC;Torbenson MS;Kleiner DE;Laird PW;Wheeler DA;McRee AJ;Bathe OF;Andersen JB;Bardeesy N;Roberts LR;Kwong LN
胆管癌(CCA)是一种侵袭性胆管恶性肿瘤，预后差，治疗选择有限。在这里，我们描述了一组以肝内CCA为主的病例的体细胞突变、RNA表达、拷贝数和DNA甲基化的综合分析，并提出了一个分子分类方案。我们发现了一个富含IDH突变的亚型，具有明显的分子特征，包括染色质修饰物的低表达，线粒体基因的表达升高，以及线粒体DNA拷贝数的增加。利用多平台数据，我们观察到ARID1A在IDH突变亚型中表现出DNA超甲基化和表达降低。更广泛地说，我们发现IDH突变与扩大的肝肿瘤组织学谱有关，其分子特征与CCA相似。我们的研究揭示了胆管细胞癌的分子发病机制和异质性，并提供了具有潜在治疗意义的分类信息。
Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.