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Proteogenomics connects somatic mutations to signalling in breast cancer

Item Type:Article
Title:Proteogenomics connects somatic mutations to signalling in breast cancer
Creators Name:Mertins, P. and Mani, D.R. and Ruggles, K.V. and Gillette, M.A. and Clauser, K.R. and Wang, P. and Wang, X. and Qiao, J.W. and Cao, S. and Petralia, F. and Kawaler, E. and Mundt, F. and Krug, K. and Tu, Z. and Lei, J.T. and Gatza, M.L. and Wilkerson, M. and Perou, C.M. and Yellapantula, V. and Huang, K.L. and Lin, C. and McLellan, M.D. and Yan, P. and Davies, S.R. and Townsend, R.R. and Skates, S.J. and Wang, J. and Zhang, B. and Kinsinger, C.R. and Mesri, M. and Rodriguez, H. and Ding, L. and Paulovich, A.G. and Fenyoe, D. and Ellis, M.J. and Carr, S.A.
Abstract:Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here 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 provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins 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. In addition to 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 the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
Keywords:Breast Neoplasms, Calcium-Binding Proteins, Chromosome Deletion, Cyclin-Dependent Kinases, Epidermal Growth Factor Receptor, ErbB-2 Receptor, Focal Adhesion Kinase 1, G-Protein-Coupled Receptors, Genomics, Human Pair 5 Chromosomes, Mass Spectrometry, Molecular Sequence Annotation, Mutation, Neoplastic Gene Expression Regulation, P21-Activated Kinases, Phosphatidylinositol 3-Kinases, Phosphoproteins, Protein Kinases, Proteomics, Receptor-Interacting Protein Serine-Threonine Kinase 2, S-Phase Kinase-Associated Proteins, Signal Transduction, Src-Family Kinases, Tumor Suppressor Protein p53
Publisher:Nature Publishing Group
Page Range:55-62
Date:2 June 2016
Official Publication:https://doi.org/10.1038/nature18003
PubMed:View item in PubMed

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