Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

作者：Karsten Krug, Eric J. Jaehnig, Shankha Satpathy, Lili M. Blumenberg, Alla Y. Karpova, Meenakshi Anurag, George Miles, Philipp Mertins, Yifat Geffen, Lauren C. Tang, David I. Heiman, Song Cao, Yosef E. Maruvka, Jonathan Thomas Lei, Chen Lu Huang, Ramani Bhupendra Kothadia, Antonio Colaprico, Chet Birger, Jarey H. Wang, Yongchao Dou, Bo Wen, Zhiao Shi, Yuxing Liao, Maciej Wiznerowicz, Matthew A. Wyczalkowski, Xi Chen, Jacob J. Kennedy, Amanda G. Paulovich, Mathangi Thiagarajan, Christopher R. Kinsinger, Tara Hiltke, Emily S. Boja, Mehdi Mesri, Ana I. Robles, Henry Rodriguez, Thomas F. Westbrook, Li Ding, Gad A. Getz, Karl R. Clauser, David Fenyö, Kelly V. Ruggles, Bing Zhang, D.R. Mani, Steven A. Carr, Matthew J. Ellis, Michael A. Gillette, Shayan C. Avanessian, Shuang Cai, Daniel Chan, Xian Chen, Nathan J Edwards, Andrew N. Hoofnagle, M. Harry Kane, Karen A. Ketchum, Eric W. Kuhn, Douglas A. Levine, Shunqiang Li, Daniel C. Liebler, Tao Liu, Jingqin Rosy Luo, Subha Madhavan, Christopher Gerard Maher, Jason McDermott, Peter B. McGarvey, Mauricio Oberti, Akhilesh Pandey, Samuel Payne, David F. Ransohoff, Robert C. Rivers, Karin Rodland, Paul A. Rudnick, Melinda E. Sanders, Kenna Mills Shaw, Ie‐Ming Shih, Robbert J.C. Slebos, Richard Smith, Michael Snyder, Stephen E. Stein, David L. Tabb, Ratna Rajesh Thangudu, Stefani N. Thomas, Yue Wang, Forest M. White, Jeffrey R. Whiteaker, Gordon A. Whiteley, Hui Zhang, Zhen Zhang, Yingming Zhao, Heng Zhu, Lisa J. Zimmerman · 发表于：Cell · 年份：2020 · DOI：10.1016/j.cell.2020.10.036 · 被引用次数：577 · 研究领域：Advanced Proteomics Techniques and Applications、Bioinformatics and Genomic Networks、Ferroptosis and cancer prognosis

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.