Proteogenomic insights suggest druggable pathways in endometrial carcinoma
Yongchao Dou, Lizabeth Katsnelson, Marina A. Gritsenko, Yingwei Hu, Boris Reva, Runyu Hong, Yi-Ting Wang, Iga Kołodziejczak, Rita Jui-Hsien Lu, Chia‐Feng Tsai, Wen Bu, Wenke Liu, Xiaofang Guo, Eunkyung An, Rebecca C. Arend, Jasmin Bavarva, Lijun Chen, Rosalie Chu, Andrzej Czekański, Teresa Davoli, Elizabeth G. Demicco, Deborah F. DeLair, Kelly A. Devereaux, Saravana M. Dhanasekaran, Peter R. Dottino, Bailee Dover, Thomas Fillmore, McKenzie E. Foxall, Catherine Hermann, Tara Hiltke, Galen Hostetter, Marcin Jędryka, Scott D. Jewell, Isabelle Johnson, Andrea G. Kahn, Amy T. Ku, Chandan Kumar‐Sinha, Paweł Kurzawa, Alexander J. Lazar, Rossana Lazcano, Jonathan T. Lei, Yi Li, Yuxing Liao, T. Mamie Lih, Tai‐Tu Lin, John A. Martignetti, Ramya P. Masand, Rafał Matkowski, Wilson McKerrow, Mehdi Mesri, Matthew Monroe, Jamie Moon, Ronald Moore, Michael Nestor, Chelsea J. Newton, Tatiana Omelchenko, Gilbert S. Omenn, Samuel Payne, Vladislav Petyuk, Ana I. Robles, Henry Rodriguez, Kelly V. Ruggles, Dmitry Rykunov, Sara R. Savage, Athena Schepmoes, Tujin Shi, Zhiao Shi, Jimin Tan, Mason D. Taylor, Mathangi Thiagarajan, Joshua M. Wang, Karl Weitz, Bo Wen, Claire Williams, Yige Wu, Matthew A. Wyczalkowski, Xinpei Yi, Xu Zhang, Rui Zhao, David G. Mutch, Arul M. Chinnaiyan, Richard Smith, Alexey I. Nesvizhskii, Pei Wang, Maciej Wiznerowicz, Li Ding, D.R. Mani, Hui Zhang, Matthew L. Anderson, Karin Rodland, Bing Zhang, Tao Liu, David Fenyö, Andrzej Antczak, Meenakshi Anurag, Thomas Bauer, Chet Birger, Michael J. Birrer, Melissa Borucki, Shuang Cai
Abstract
We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.