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Proteogenomic landscape of breast cancer tumorigenesis and targeted therapy

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Item Type:Article
Title:Proteogenomic landscape of breast cancer tumorigenesis and targeted therapy
Creators Name:Krug, K. and Jaehnig, E.J. and Satpathy, S. and Blumenberg, L. and Karpova, A. and Anurag, M. and Miles, G. and Mertins, P. and Geffen, Y. and Tang, L.C. and Heiman, D.I. and Cao, S. and Maruvka, Y.E. and Lei, J.T. and Huang, C. and Kothadia, R.B. and Colaprico, A. and Birger, C. and Wang, J. and Dou, Y. and Wen, B. and Shi, Z. and Liao, Y. and Wiznerowicz, M. and Wyczalkowski, M.A. and Chen, X.S. and Kennedy, J.J. and Paulovich, A.G. and Thiagarajan, M. and Kinsinger, C.R. and Hiltke, T. and Boja, E.S. and Mesri, M. and Robles, A.I. and Rodriguez, H. and Westbrook, T.F. and Ding, L. and Getz, G. and Clauser, K.R. and Fenyö, D. and Ruggles, K.V. and Zhang, B. and Mani, D.R and Carr, S.A. and Ellis, M.J. and Gillette, M.A.
Abstract:The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.
Keywords:CPTAC, Proteogenomics, Breast Cancer, Genomics, Proteomics, Phosphoproteomics, Acetylation, Mass Spectrometry, Immune Checkpoint Therapy, CDK 4/6 Inhibitors
Source:Cell
ISSN:0092-8674
Publisher:Cell Press
Volume:183
Number:5
Page Range:1436-1456
Date:25 November 2020
Official Publication:https://doi.org/10.1016/j.cell.2020.10.036
PubMed:View item in PubMed

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