Proteogenomics connects somatic mutations to signalling in breast cancer

Philipp Mertins (), D. R. Mani, Kelly V. Ruggles, Michael A. Gillette, Karl R. Clauser, Pei Wang, Xianlong Wang, Jana W. Qiao, Song Cao, Francesca Petralia, Emily Kawaler, Filip Mundt, Karsten Krug, Zhidong Tu, Jonathan T. Lei, Michael L. Gatza, Matthew Wilkerson, Charles M. Perou, Venkata Yellapantula, Kuan-lin Huang, Chenwei Lin, Michael D. McLellan, Ping Yan, Sherri R. Davies, R. Reid Townsend, Steven J. Skates, Jing Wang, Bing Zhang, Christopher R. Kinsinger, Mehdi Mesri, Henry Rodriguez, Li Ding, Amanda G. Paulovich, David Fenyö, Matthew J. Ellis () and Steven A. Carr ()
Additional contact information
Philipp Mertins: The Broad Institute of MIT and Harvard, Cambridge
D. R. Mani: The Broad Institute of MIT and Harvard, Cambridge
Kelly V. Ruggles: New York University Langone Medical Center
Michael A. Gillette: The Broad Institute of MIT and Harvard, Cambridge
Karl R. Clauser: The Broad Institute of MIT and Harvard, Cambridge
Pei Wang: Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai New York
Xianlong Wang: Fred Hutchinson Cancer Research Center, Seattle
Jana W. Qiao: The Broad Institute of MIT and Harvard, Cambridge
Song Cao: McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine
Francesca Petralia: Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai New York
Emily Kawaler: New York University Langone Medical Center
Filip Mundt: The Broad Institute of MIT and Harvard, Cambridge
Karsten Krug: The Broad Institute of MIT and Harvard, Cambridge
Zhidong Tu: Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai New York
Jonathan T. Lei: Lester and Sue Smith Breast Center, Baylor College of Medicine
Michael L. Gatza: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Matthew Wilkerson: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Charles M. Perou: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Venkata Yellapantula: McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine
Kuan-lin Huang: McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine
Chenwei Lin: Fred Hutchinson Cancer Research Center, Seattle
Michael D. McLellan: McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine
Ping Yan: Fred Hutchinson Cancer Research Center, Seattle
Sherri R. Davies: Washington University School of Medicine
R. Reid Townsend: Washington University School of Medicine
Steven J. Skates: Biostatistics Center, Massachusetts General Hospital Cancer Center, Boston
Jing Wang: Vanderbilt University School of Medicine
Bing Zhang: Vanderbilt University School of Medicine
Christopher R. Kinsinger: National Cancer Institute, National Institutes of Health
Mehdi Mesri: National Cancer Institute, National Institutes of Health
Henry Rodriguez: National Cancer Institute, National Institutes of Health
Li Ding: McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine
Amanda G. Paulovich: Fred Hutchinson Cancer Research Center, Seattle
David Fenyö: New York University Langone Medical Center
Matthew J. Ellis: Lester and Sue Smith Breast Center, Baylor College of Medicine
Steven A. Carr: The Broad Institute of MIT and Harvard, Cambridge

Nature, 2016, vol. 534, issue 7605, 55-62

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature18003

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