Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma
Authors: Chen Huang, Lijun Chen, Sara R. Savage, Rodrigo Vargas Eguez, Yongchao Dou, Yize Li, Felipe da Veiga Leprevost, Eric J. Jaehnig, Jonathan T. Lei, Bo Wen, Michael Schnaubelt, Karsten Krug, Xiaoyu Song, Marcin Cieślik, Hui-Yin Chang, Matthew A. Wyczalkowski, Kai Li, Antonio Colaprico, Qing Kay Li, David J. Clark, Yingwei Hu, Liwei Cao, Jianbo Pan, Yuefan Wang, Kyung-Cho Cho, Zhiao Shi, Yuxing Liao, Wen Jiang, Meenakshi Anurag, Jiayi Ji, Seungyeul Yoo, Daniel Cui Zhou, Wen-Wei Liang, Michael Wendl, Pankaj Vats, Steven A. Carr, D.R. Mani, Zhen Zhang, Jiang Qian, Xi S. Chen, Alexander R. Pico, Pei Wang, Arul M. Chinnaiyan, Karen A. Ketchum, Christopher R. Kinsinger, Ana I. Robles, Eunkyung An, Tara Hiltke, Mehdi Mesri, Mathangi Thiagarajan, Alissa M. Weaver, Andrew G. Sikora, Jan Lubiński, Małgorzata Wierzbicka, Maciej Wiznerowicz, Shankha Satpathy, Michael A. Gillette, George Miles, Matthew J. Ellis, Gilbert S. Omenn, Henry Rodriguez, Emily S. Boja, Saravana M. Dhanasekaran, Li Ding, Alexey I. Nesvizhskii, Adel K. El-Naggar, Daniel W. Chan, Hui Zhang, Bing Zhang, Anupriya Agarwal, Matthew L. Anderson, Shayan C. Avanessian, Dmitry Avtonomov, Oliver F. Bathe, Chet Birger, Michael J. Birrer, Lili Blumenberg, William E. Bocik, Uma Borate, Melissa Borucki, Meghan C. Burke, Shuang Cai, Anna Pamela Calinawan, Sandra Cerda, Alyssa Charamut, Lin S. Chen, Shrabanti Chowdhury, Karl R. Clauser, Houston Culpepper, Tomasz Czernicki, Fulvio D'Angelo, Jacob Day, Stephanie De Young, Emek Demir, Fei Ding, Marcin J. Domagalski, Joseph C. Dort, Brian Druker, Elizabeth Duffy, Maureen Dyer, Nathan J. Edwards, Kimberly Elburn, Tatiana S. Ermakova, David Fenyo, Renata Ferrarotto, Alicia Francis, Stacey Gabriel, Luciano Garofano, Yifat Geffen, Gad Getz, Charles A. Goldthwaite, Linda I. Hannick, Pushpa Hariharan, David N. Hayes, David Heiman, Barbara Hindenach, Katherine A. Hoadley, Galen Hostetter, Martin Hyrcza, Scott D. Jewell, Corbin D. Jones, M. Harry Kane, Alicia Karz, Ramani B. Kothadia, Azra Krek, Chandan Kumar-Sinha, Tao Liu, Hongwei Liu, Weiping Ma, Ewa Malc, Anna Malovannaya, Sailaja Mareedu, Sanford P. Markey, Annette Marrero-Oliveras, Nicollette Maunganidze, Jason E. McDermott, Peter B. McGarvey, John McGee, Piotr Mieczkowski, Simona Migliozzi, Rebecca Montgomery, Chelsea J. Newton, Umut Ozbek, Amanda G. Paulovich, Samuel H. Payne, Dimitar Dimitrov Pazardzhikliev, Amy M. Perou, Francesca Petralia, Lyudmila Petrenko, Paul D. Piehowski, Dmitris Placantonakis, Larisa Polonskaya, Elena V. Ponomareva, Olga Potapova, Liqun Qi, Ning Qu, Shakti Ramkissoon, Boris Reva, Shannon Richey, Karna Robinson, Nancy Roche, Karin Rodland, Daniel C. Rohrer, Dmitry Rykunov, Eric E. Schadt, Yan Shi, Yvonne Shutack, Shilpi Singh, Tara Skelly, Richard Smith, Lori J. Sokoll, Jakub Stawicki, Stephen E. Stein, James Suh, Wojciech Szopa, Dave Tabor, Donghui Tan, Darlene Tansil, Guo Ci Teo, Ratna R. Thangudu, Cristina Tognon, Elie Traer, Shirley Tsang, Jeffrey Tyner, Ki Sung Um, Dana R. Valley, Lyubomir Valkov Vasilev, Negin Vatanian, Uma Velvulou, Michael Vernon, Thomas F. Westbrook, Jeffrey R. Whiteaker, Yige Wu, Midie Xu, Lijun Yao, Xinpei Yi, Fengchao Yu, Kakhaber Zaalishvili, Yuriy Zakhartsev, Robert Zelt, Grace Zhao, Jun Zhu
Journal: Cancer Cell (2021)

We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins and phosphosites, prioritizes copy number drivers, and highlights an oncogenic role for RNA processing genes. Proteomic investigation of mutual exclusivity between FAT1 truncating mutations and 11q13.3 amplifications reveals dysregulated actin dynamics as a common functional consequence. Phosphoproteomics characterizes two modes of EGFR activation, suggesting a new strategy to stratify HNSCCs based on EGFR ligand abundance for effective treatment with inhibitory EGFR monoclonal antibodies. Widespread deletion of immune modulatory genes accounts for low immune infiltration in immune-cold tumors, whereas concordant upregulation of multiple immune checkpoint proteins may underlie resistance to anti-programmed cell death protein 1 monotherapy in immune-hot tumors. Multi-omic analysis identifies three molecular subtypes with high potential for treatment with CDK inhibitors, anti-EGFR antibody therapy, and immunotherapy, respectively. Altogether, proteogenomics provides a systematic framework to inform HNSCC biology and treatment.