title: Proteogenomics connects somatic mutations to signalling in breast cancer.
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.
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Mertins
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Mani
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York 10016, USA.
authors.forename: Kelly V
authors.initials: KV
authors.lastname: Ruggles
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gillette
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Karl R
authors.initials: KR
authors.lastname: Clauser
authors.affiliation: 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.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Xianlong
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Jana W
authors.initials: JW
authors.lastname: Qiao
authors.affiliation: Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Cao
authors.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Petralia
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York 10016, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Kawaler
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Department of Oncology-Pathology, Karolinska Institute, 171 76 Stockholm, Sweden.
authors.forename: Filip
authors.initials: F
authors.lastname: Mundt
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Krug
authors.affiliation: 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.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Tu
authors.affiliation: 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.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Lei
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Gatza
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wilkerson
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
authors.forename: Venkata
authors.initials: V
authors.lastname: Yellapantula
authors.affiliation: Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
authors.forename: Kuan-lin
authors.initials: KL
authors.lastname: Huang
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Chenwei
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yan
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Sherri R
authors.initials: SR
authors.lastname: Davies
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.affiliation: Biostatistics Center, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Skates
authors.affiliation: Department of Biomedical Informatics and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biomedical Informatics and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Kinsinger
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mesri
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Rodriguez
authors.affiliation: Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Paulovich
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York 10016, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fenyö
authors.affiliation: 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.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
mesh_terms: D001943:Breast Neoplasms / Q000145:classification / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D013058:Mass Spectrometry; D058977:Molecular Sequence Annotation; D009154:Mutation / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D018844:Cyclin-Dependent Kinases; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011494:Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D043562:Receptors, G-Protein-Coupled; D044786:S-Phase Kinase-Associated Proteins; D016159:Tumor Suppressor Protein p53; D054462:p21-Activated Kinases; D019061:src-Family Kinases; C107745:CETN3 protein, human; C097351:SKP1 protein, human; C495901:TP53 protein, human; C121377:protein kinase U; C484760:PIK3CA protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C496050:PTK2 protein, human; C515903:PAK1 protein, human; C506253:RIPK2 protein, human; C447339:CDK12 protein, human