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Nature. 2016 Jun 2;534(7605):55-62. doi: 10.1038/nature18003. Epub 2016 May 25.

Proteogenomics connects somatic mutations to signalling in breast cancer.

Author information

1
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
2
Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York 10016, USA.
3
Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
4
Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai New York, New York 10029, USA.
5
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
6
Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
7
Department of Oncology-Pathology, Karolinska Institute, 171 76 Stockholm, Sweden.
8
Lester and Sue Smith Breast Center, Dan L. Duncan Comprehensive Cancer Center and Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
9
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
10
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
11
Biostatistics Center, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
12
Department of Biomedical Informatics and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
13
National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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.

PMID:
27251275
PMCID:
PMC5102256
DOI:
10.1038/nature18003
[Indexed for MEDLINE]
Free PMC Article

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