Proteogenomic Characterization of Endometrial Carcinoma

• Published in: Cell 2020-02, Vol.180 (4), p.729-748.e26
• Main Authors: Kawaler, Emily A., Cui Zhou, Daniel, Huang, Chen, Blumenberg, Lili, Karpova, Alla, Petyuk, Vladislav A., Wen, Bo, Li, Zhi, Cao, Song, Moon, Jamie, Shi, Zhiao, Cornwell, MacIntosh, Wyczalkowski, Matthew A., Chu, Rosalie K., Gao, Qingsong, Moore, Ronald J., Li, Kai, Zhao, Rui, Clauser, Karl, Maruvka, Yosef, Pico, Alexander R., Beecroft, Sean J.I., Adams, David W., Liao, Yuxing, Rykunov, Dmitry, Czekański, Andrzej, Jędryka, Marcin, Kinsinger, Christopher R., Mesri, Mehdi, Ellis, Matthew J., Thiagarajan, Mathangi, Noble, Michael, Wang, Pei, Anderson, Matthew L., Levine, Douglas A., Rodland, Karin D., Liu, Tao, Birger, Chet, Birrer, Michael J., Bocik, William E., Borate, Uma, Cai, Shuang, Carter, Sonya, Castro, Patricia, Chaikin, Michelle, Chen, Jin, Chesla, David, Chheda, Milan G., Culpepper, Houston, Demir, Emek, Dhir, Rajiv, Domagalski, Marcin J., Edwards, Robert, Elburn, Kim, Field, Jayson B., Gabriel, Stacey, Godwin, Andrew K., Grady, Pamela, Hariharan, Pushpa, Hoadley, Katherine A., Hostetter, Galen, Hu, Yingwei, Jaehnig, Eric, Jewell, Scott D., Ji, Jiayi, Jones, Corbin D., Karabon, Renee, Ketchum, Karen A., Krubit, Tanya, Leprevost, Felipe D., Lewis, Michael, Ma, Weiping, Madan, Rashna, Markey, Sanford P., McDermott, Jason, McGarvey, Peter B., Modugno, Francesmary, Montgomery, Rebecca, Piehowski, Paul, Polonskaya, Larisa, Qi, Liqun, Schadt, Eric E., Shi, Yan, Skelly, Tara, Stein, Stephen E., Tan, Donghui, Teo, Guo Ci, Thangudu, Ratna R., Valley, Dana R., Vernon, Michael, Wang, Ying, Webster, Alex, Westbrook, Thomas, Wheeler, David, Wilson, George D., Zelt, Robert, Zhang, Hui, Zhang, Yuping, Zhang, Zhen, Zhao, Grace
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Antigens, Neoplasm - genetics; BASIC BIOLOGICAL SCIENCES; Carcinoma - genetics; Carcinoma - immunology; Carcinoma - pathology; circular RNA; CTNNB1; endometrial cancer; Endometrial Neoplasms - genetics; Endometrial Neoplasms - immunology; Endometrial Neoplasms - pathology; endometrioid endometrial cancer; Epithelial-Mesenchymal Transition - genetics; Feedback, Physiological; Female; Gene Expression Regulation, Neoplastic; Genomic Instability; Humans; immune evasion; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Microsatellite Repeats; Phosphorylation; Protein Processing, Post-Translational; proteogenomics; Proteome - genetics; Proteome - metabolism; proteomics; serous endometrial cancer; Signal Transduction; TP53; Transcriptome
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2020.01.026

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets. [Display omitted] •Proteogenomics provides new insights into oncogenic signaling in endometrial carcinoma•Global acetylome and phosphoproteome surveys identify new regulatory mechanisms•QKI, circRNAs, and miRNAs form a potential feedback loop to promote EMT•Antigen presentation defects may render MSI tumors resistant to checkpoint blockade Proteogenomic analyses of prospectively collected endometrial carcinomas provide insights into the role of underlying molecular pathways and the immune landscape that drive disease.