Proteogenomics connects somatic mutations to signalling in breast cancer.
Proteogenomics connects somatic mutations to signalling in breast cancer.
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DOI：
10.1038/nature18003
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发表时间：
2016-06-02
期刊：
影响因子：
64.8
通讯作者：
Carr, Steven A.
中科院分区：
文献类型：
--
作者：
Mertins, Philipp;Mani, D. R.;Ruggles, Kelly V.;Gillette, Michael A.;Clauser, Karl R.;Wang, Pei;Wang, Xianlong;Qiao, Jana W.;Cao, Song;Petralia, Francesca;Kawaler, Emily;Mundt, Filip;Krug, Karsten;Tu, Zhidong;Lei, Jonathan T.;Gatza, Michael L.;Wilkerson, Matthew;Perou, Charles M.;Yellapantula, Venkata;Huang, Kuan-lin;Lin, Chenwei;McLellan, Michael D.;Yan, Ping;Davies, Sherri R.;Townsend, R. Reid;Skates, Steven J.;Wang, Jing;Zhang, Bing;Kinsinger, Christopher R.;Mesri, Mehdi;Rodriguez, Henry;Ding, Li;Paulovich, Amanda G.;Fenyo, David;Ellis, Matthew J.;Carr, Steven A.
体细胞突变在乳腺癌中有广泛的特征，但这些基因改变对蛋白质组图景的影响仍然知之甚少。我们描述了105个基因组注释的乳腺癌的基于定量质谱学的蛋白质组和磷蛋白质组分析，其中77个提供了高质量的数据。综合分析使人们能够深入了解体细胞癌基因组，包括染色体丢失的后果，例如基底样乳腺癌的5q缺失特征。根据整合的基于网络的细胞特征库询问5q反式效应，从而将CETN3和Skp1缺失与EGFR的表达上调联系起来，Skp1缺失也与SRC增加有关。全球蛋白质组学数据证实，除了基础和管腔簇外，还有一个基质丰富的组，对磷蛋白质组的通路分析发现了一个G蛋白偶联受体簇，但在mRNA水平上并不容易识别。除ERBB2外，还发现了CDK12、PAK1、PTK2、RIPK2和TLK2等与扩增子相关的高度磷酸化的激酶。我们证明，乳腺癌的蛋白质基因组分析阐明了体细胞突变的功能后果，缩小了大片段缺失和扩增区域内驱动基因的候选提名，并确定了治疗靶点。
Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. We describe quantitative mass spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers of which 77 provided high-quality data. Integrated analyses allowed insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. The 5q trans effects were interrogated against the Library of Integrated Network-based Cellular Signatures, thereby connecting CETN3 and SKP1 loss to elevated expression of EGFR, and SKP1 loss also to increased SRC. Global proteomic data confirmed a stromal-enriched group in addition to basal and luminal clusters and pathway analysis of the phosphoproteome identified a G Protein-coupled receptor cluster that was not readily identified at the mRNA level. Besides ERBB2, other amplicon-associated, highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
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