Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

• Published in: Cell Vol. 183; no. 5; pp. 1436 - 1456.e31
• Main Authors: Krug, Karsten, Jaehnig, Eric J., Satpathy, Shankha, Blumenberg, Lili, Karpova, Alla, Anurag, Meenakshi, Miles, George, Mertins, Philipp, Geffen, Yifat, Tang, Lauren C., Heiman, David I., Cao, Song, Maruvka, Yosef E., Lei, Jonathan T., Huang, Chen, Kothadia, Ramani B., Colaprico, Antonio, Birger, Chet, Wang, Jarey, Dou, Yongchao, Wen, Bo, Shi, Zhiao, Liao, Yuxing, Wiznerowicz, Maciej, Wyczalkowski, Matthew A., Chen, Xi Steven, Kennedy, Jacob J., Paulovich, Amanda G., Thiagarajan, Mathangi, Kinsinger, Christopher R., Hiltke, Tara, Boja, Emily S., Mesri, Mehdi, Robles, Ana I., Rodriguez, Henry, Westbrook, Thomas F., Ding, Li, Getz, Gad, Clauser, Karl R., Fenyö, David, Ruggles, Kelly V., Zhang, Bing, Mani, D.R., Carr, Steven A., Ellis, Matthew J., Gillette, Michael A., Avanessian, Shayan C., Cai, Shuang, Chan, Daniel, Chen, Xian, Edwards, Nathan J., Hoofnagle, Andrew N., Kane, M. Harry, Ketchum, Karen A., Kuhn, Eric, Levine, Douglas A., Li, Shunqiang, Liebler, Daniel C., Liu, Tao, Luo, Jingqin, Madhavan, Subha, Maher, Chris, McDermott, Jason E., McGarvey, Peter B., Oberti, Mauricio, Pandey, Akhilesh, Payne, Samuel H., Ransohoff, David F., Rivers, Robert C., Rodland, Karin D., Rudnick, Paul, Sanders, Melinda E., Shaw, Kenna M., Shih, Ie-Ming, Slebos, Robbert J.C., Smith, Richard D., Snyder, Michael, Stein, Stephen E., Tabb, David L., Thangudu, Ratna R., Thomas, Stefani, Wang, Yue, White, Forest M., Whiteaker, Jeffrey R., Whiteley, Gordon A., Zhang, Hui, Zhang, Zhen, Zhao, Yingming, Zhu, Heng, Zimmerman, Lisa J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-11-2020
• Subjects: acetylation; Adult; Aged; Aged, 80 and over; APOBEC Deaminases - metabolism; breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Carcinogenesis - genetics; Carcinogenesis - pathology; CDK 4/6 inhibitors; Cohort Studies; CPTAC; DNA Damage; DNA Repair; Female; genomics; Humans; immune checkpoint therapy; Immunotherapy; mass spectrometry; Metabolomics; Middle Aged; Molecular Targeted Therapy; Mutagenesis - genetics; phosphoproteomics; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Proteogenomics; proteomics; Receptor, ErbB-2 - metabolism; Retinoblastoma Protein - metabolism; Tumor Microenvironment - immunology; phosphoproteomics; acetylation; proteomics; immune checkpoint therapy; breast cancer; genomics; mass spectrometry; CPTAC; proteogenomics; CDK 4/6 inhibitors
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.10.036

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.
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•Comprehensive proteogenomics resource from prospectively collected breast tumors•Proteogenomics defines ERBB2 and Rb status with clinical implications•Acetylproteome profiling yields insights into subtype-specific cancer metabolism•Immune profiling nominates subsets of luminal tumors for immune therapy
Breast cancer is a highly heterogeneous disease with variable outcomes and subtype-driven treatment approaches, making precision medicine a considerable challenge. Proteogenomic analyses of 122 primary breast cancers provide insights into clinically relevant biology, including cell cycle dysregulation, tumor immunogenicity, aberrant metabolism, and heterogeneity in therapeutic target expression.