Liang-BoWang, Alla Karpova, Marina A. Gritsenko, Jennifer E. Kyle, Song Cao, Yize Li, DmitryRykunov, Antonio Colaprico, Joseph H. Rothstein, Runyu Hong, Vasileios Stathias, MacIntoshCornwell, Francesca Petralia, Yige Wu, Boris Reva, Karsten Krug, Pietro Pugliese, Emily Kawaler, Lindsey K.Olsen, Wen-Wei Liang, Xiaoyu Song, Yongchao Dou, Michael C. Wendl, Wagma Caravan, Wenke Liu, Daniel Cui Zhou, Jiayi Ji, Chia-Feng Tsai, Vladislav A. Petyuk, Jamie Moon, Weiping Ma, Rosalie K. Chu, Karl K. Weitz, Ronald J.Moore, Matthew E. Monroe, Rui Zhao, Xiaolu Yang, Seungyeul Yoo, Azra Krek, Alexis Demopoulos, Houxiang Zhu, Matthew A. Wyczalkowski, Joshua F. McMichael, Brittany L. Henderson, Caleb M. Lindgren, Hannah Boekweg, Shuangjia Lu, Jessika Baral, Lijun Yao, Kelly G. Stratton, Lisa M. Bramer, Erika Zink, Sneha P. Couvillion, Kent J. Bloodsworth, Shankha Satpathy, Weiva Sieh, Simina M. Boca, Stephan Schürer, Feng Chen, Maciej Wiznerowicz, Karen A. Ketchum, Emily S. Boja, Christopher R. Kinsinger, Ana I. Robles, Tara Hiltke, Mathangi Thiagarajan, Alexey I. Nesvizhskii, Bing Zhang, D. R. Mani, Michele Ceccarelli, Xi S. Chen, Sandra L.Cottingham34Qing KayLi35Albert H.Kim36DavidFenyö, Kelly V. Ruggles, Henry Rodriguez, Mehdi Mesri, Samuel H. Payne, Adam C. Resnick, Pei Wang, Richard D. Smith, Antonio Iavarone, Milan G. Chheda, Jill S. Barnholtz-Sloan, Karin D. Rodland, Tao Liu, Li Ding, Clinical Proteomic Tumor Analysis Consortium Anupriya Agarwal, Mitual Amin, Eunkyung An, Matthew L.Anderson, David W.Andrews, Thomas Bauer, Chet Birger, Michael J.Birrer, Lili Blumenberg, William E.Bocik, Uma Borate, Melissa Borucki, Meghan C.Burke, Shuang Cai, Anna P.Calinawan, Steven A.Carr, Sandra Cerda, Daniel W.Chan, Alyssa Charamut, Lin S.Chen, David Chesla, Arul M.Chinnaiyan, ShrabantiChowdhury, Marcin P.Cieślik, David J.Clark, HoustonCulpepper, TomaszCzernicki, FulvioD'Angelo, JacobDay, Stephanie De Young, EmekDemir, Saravana Mohan, Dhanasekaran, Rajiv Dhir, Marcin J.Domagalski, BrianDruker, ElizabethDuffy, MaureenDyer, Nathan J.Edwards, RobertEdwards, KimberlyElburn, Matthew J.Ellis, JenniferEschbacher, AliciaFrancis, Stacey Gabriel, Nikolay Gabrovski, Luciano Garofano, Gad Getz, Michael A.Gillette, Andrew K.Godwin, Denis Golbin, Ziad Hanhan, Linda I.Hannick, Pushpa Hariharan, Barbara Hindenach, Katherine A.Hoadley, Galen Hostetter, Chen Huang, Eric Jaehnig, Scott D.Jewell, Nan Ji, Corbin D.Jones, Alcida Karz, Wojciech Kaspera, Lyndon Kim, Ramani B.Kothadia, Chandan Kumar-Sinha, Jonathan Lei, Felipe D.Leprevost, KaiLi, Yuxing Liao, Jena Lilly, Hongwei Liu, Jan Lubínski, Rashna Madan, William Maggio, Ewa Malc, Anna Malovannaya, Sailaja Mareedu, Sanford P.Markey, AnnetteMarrero-Oliveras, NinaMartinez, Nicollette Maunganidze, Jason E.McDermott, Peter B.McGarvey, John McGee, Piotr Mieczkowski, Simona Migliozzi, Francesmary Modugno, Rebecca Montgomery, Chelsea J.Newton, Gilbert S.Omenn, UmutOzbek, Oxana V.Paklina, Amanda G.Paulovich, Amy M.Perou, Alexander R.Pico, Paul D.Piehowski, Dimitris G.Placantonakis, LarisaPolonskaya, Olga Potapova, BarbaraPruetz, Liqun Qi, Shakti Ramkissoon, Adam Resnick, Shannon Richey, Gregory Riggins, Karna Robinson, Nancy Roche, Daniel C.Rohrer, Brian R.Rood, Larissa Rossell, Sara R.Savage, Eric E.Schadt, Yan Shi, Zhiao Shi, Yvonne Shutack, Shilpi Singh, Tara Skelly, Lori J.Sokoll, Jakub Stawicki, Stephen E.Stein, James Suh, Wojciech Szopa, Dave Tabor, Donghui Tan, Darlene Tansil, Ratna R.Thangudu, Cristina Tognon, Elie Traer, Shirley Tsang, Jeffrey Tyner, Ki SungUm, Dana R.Valley, Suhas Vasaikar, Negin Vatanian, Uma Velvulou, Michael Vernon, Weiqing Wan, Junmei Wang, Alex Webster, Bo Wen, Jeffrey R.Whiteaker, George D.Wilson, Yuriy Zakhartsev, Robert Zelt, Hui Zhang, Liwei Zhang, Zhen Zhang, Grace Zhao, Jun Zhu
Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment.
Acknowledgements
This work was supported by grants U24CA210972, U24CA210955, U24CA210954, U24CA210985, U24CA210993, U24CA210967, U24CA210986, U01CA214125, and U24CA210979 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium, by grant R01HG009711 from National Human Genome Research Institute to L.D., and R01NS107833 from National Institutes of Health to M.G.C. The MS-based proteomics work was performed at the Environmental Molecular Sciences Laboratory (grid.436923.9), a U.S. Department of Energy National Scientific User Facility located at the Pacific Northwest National Laboratory operated under contract DE-AC05-76RL01830. We thank Dr. Charles A. Goldthwaite for manuscript editing.
