Farshidfar Farshad, Zheng Siyuan, Gingras Marie-Claude, Newton Yulia, Shih Juliann, Robertson A Gordon, Hinoue Toshinori, Hoadley Katherine A, Gibb Ewan A, Roszik Jason, Covington Kyle R, Wu Chia-Chin, Shinbrot Eve, Stransky Nicolas, Hegde Apurva, Yang Ju Dong, Reznik Ed, Sadeghi Sara, Pedamallu Chandra Sekhar, Ojesina Akinyemi I, Hess Julian M, Auman J Todd, Rhie Suhn K, Bowlby Reanne, Borad Mitesh J, Zhu Andrew X, Stuart Josh M, Sander Chris, Akbani Rehan, Cherniack Andrew D, Deshpande Vikram, Mounajjed Taofic, Foo Wai Chin, Torbenson Michael S, Kleiner David E, Laird Peter W, Wheeler David A, McRee Autumn J, Bathe Oliver F, Andersen Jesper B, Bardeesy Nabeel, Roberts Lewis R, Kwong Lawrence N
Cell Rep. 2017 Jun 27;19(13):2878-2880. doi: 10.1016/j.celrep.2017.06.008.
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 -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 -mutant subtype. More broadly, we found that 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.
胆管癌（CCA）是一种侵袭性胆管恶性肿瘤，预后较差且治疗选择有限。在此，我们描述了癌症基因组图谱（The Cancer Genome Atlas）对一组主要为肝内胆管癌病例进行的体细胞突变、RNA表达、拷贝数和DNA甲基化的综合分析，并提出了一种分子分类方案。我们鉴定出一种富含突变的亚型，其具有独特的分子特征，包括染色质修饰因子低表达、线粒体基因表达升高以及线粒体DNA拷贝数增加。利用多平台数据，我们观察到ARID1A在该富含突变的亚型中表现出DNA高甲基化和表达降低。更广泛地说，我们发现这些突变与具有与胆管癌分层的分子特征的肝脏肿瘤组织学谱扩展相关。我们的研究揭示了胆管癌分子发病机制和异质性的见解，并提供了具有潜在治疗意义的分类信息。
