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1. Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness

Author

Yize Li, Tung-Shing M. Lih, Saravana M. Dhanasekaran, Rahul Mannan, Lijun Chen, Marcin Cieslik, Yige Wu, Rita Jiu-Hsien Lu, David J. Clark, Iga Kołodziejczak, Runyu Hong, Siqi Chen, Yanyan Zhao, Seema Chugh, Wagma Caravan, Nataly Naser Al Deen, Noshad Hosseini, Chelsea J. Newton, Karsten Krug, Yuanwei Xu, Kyung-Cho Cho, Yingwei Hu, Yuping Zhang, Chandan Kumar-Sinha, Weiping Ma, Anna Calinawan, Matthew A. Wyczalkowski, Michael C. Wendl, Yuefan Wang, Shenghao Guo, Cissy Zhang, Anne Le, Aniket Dagar, Alex Hopkins, Hanbyul Cho, Felipe da Veiga Leprevost, Xiaojun Jing, Guo Ci Teo, Wenke Liu, Melissa A. Reimers, Russell Pachynski, Alexander J. Lazar, Arul M. Chinnaiyan, Brian A. Van Tine, Bing Zhang, Karin D. Rodland, Gad Getz, D.R. Mani, Pei Wang, Feng Chen, Galen Hostetter, Mathangi Thiagarajan, W. Marston Linehan, David Fenyö, Scott D. Jewell, Gilbert S. Omenn, Rohit Mehra, Maciej Wiznerowicz, Ana I. Robles, Mehdi Mesri, Tara Hiltke, Eunkyung An, Henry Rodriguez, Daniel W. Chan, Christopher J. Ricketts, Alexey I. Nesvizhskii, Hui Zhang, Li Ding, Alicia Francis, Amanda G. Paulovich, Andrzej Antczak, Anthony Green, Antonio Colaprico, Ari Hakimi, Barb Pruetz, Barbara Hindenach, Birendra Kumar Yadav, Boris Reva, Brenda Fevrier-Sullivan, Brian J. Druker, Cezary Szczylik, Charles A. Goldthwaite, Chet Birger, Corbin D. Jones, Daniel C. Rohrer, Darlene Tansil, David Chesla, David Heiman, Elizabeth Duffy, Eri E. Schadt, Francesca Petralia, Gabriel Bromiński, Gabriela M. Quiroga-Garza, George D. Wilson, Ginny Xiaohe Li, Grace Zhao, Yi Hsiao, James Hsieh, Jan Lubiński, Jasmin Bavarva, Jasmine Huang, Jason Hafron, Jennifer Eschbacher, Jennifer Hon, Jesse Francis, John Freymann, Josh Vo, Joshua Wang, Justin Kirby, Kakhaber Zaalishvili, Karen A. Ketchum, Katherine A. Hoadley, Ki Sung Um, Liqun Qi, Marcin J. Domagalski, Matt Tobin, Maureen Dyer, Meenakshi Anurag, Melissa Borucki, Michael A. Gillette, Michael J. Birrer, Michael M. Ittmann, Michael H. Roehrl, Michael Schnaubelt, Michael Smith, Mina Fam, Nancy Roche, Negin Vatanian, Nicollette Maunganidze, Olga Potapova, Oxana V. Paklina, Pamela VanderKolk, Patricia Castro, Paweł Kurzawa, Pushpa Hariharan, Qin Li, Qing Kay Li, Rajiv Dhir, Ratna R. Thangudu, Rebecca Montgomery, Richard D. Smith, Sailaja Mareedu, Samuel H. Payne, Sandra Cerda, Sandra Cottingham, Sarah Haynes, Shankha Satpathy, Shannon Richey, Shilpi Singh, Shirley X. Tsang, Shuang Cai, Song Cao, Stacey Gabriel, Steven A. Carr, Tao Liu, Thomas Bauer, Toan Le, Xi S. Chen, Xu Zhang, Yvonne Shutack, and Zhen Zhang

Subjects
Cancer Research, Oncology
Abstract

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.

Published
2023
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2. Proteogenomic Characterization of Pancreatic Ductal Adenocarcinoma

Author

Marcin J. Domagalski, Wen Jiang, Michael Smith, Li Ding, Michael Schnaubelt, Oxana Paklina, Gilbert S. Omenn, Magdalena Derejska, Karin D. Rodland, Johanna Gardner, Saravana M. Dhanasekaran, Pamela Grady, Pushpa Hariharan, David Mallery, Jesse Francis, Maciej Wiznerowicz, Eunkyung An, Nancy Roche, Ralph H. Hruban, Samuel H. Payne, Chen Huang, Olga Potapova, Gad Getz, Zhiao Shi, Shuai Guo, Oliver F. Bathe, Stacey Gabriel, Sandra Cottingham, Hui Zhang, Daniel Cui Zhou, Maureen Dyer, Houxiang Zhu, James Suh, Shuang Cai, Christopher R. Kinsinger, Felipe da Veiga Leprevost, Steven Chen, Chelsea J. Newton, Amanda G. Paulovich, Steven A. Carr, Melissa Borucki, Sandra Cerda, Troy Shelton, D. R. Mani, Tara Hiltke, Lijun Chen, Benjamin Haibe-Kains, Jiang Long, Ratna R. Thangudu, Arul M. Chinnaiyan, Mathangi Thiagarajan, Negin Vatanian, Peter Ronning, Thomas L. Bauer, Ki Sung Um, Christina Ayad, Seungyeul Yoo, Mitual Amin, Ruiyang Liu, Alicia Francis, Nikolay Gabrovski, Eric E. Schadt, Zhen Zhang, Alexey I. Nesvizhskii, Hariharan Easwaran, Huan Chen, Tao Liu, Elizabeth R. Duffy, Liwei Cao, Joshua M. Wang, Michael H.A. Roehrl, Antonio Colaprico, Ana I. Robles, Emily S. Boja, Rita Jui-Hsien Lu, Rodrigo Vargas Eguez, Yize Li, Jennifer M. Koziak, Wenke Liu, Weiming Yang, Arvind Singh Mer, Dana R. Valley, Sailaja Mareedu, Song Cao, Scott D. Jewell, William Bocik, Shilpi Singh, Yongchao Dou, Matthew A. Wyczalkowski, David Fenyö, Galen Hostetter, Liqun Qi, Wenyi Wang, Yvonne Shutack, Shirley Tsang, Karen A. Ketchum, Charles A. Goldthwaite, Katherine A. Hoadley, Richard D. Smith, Karsten Krug, Yuxing Liao, Nadezhda V. Terekhanova, Henry Rodriguez, Barbara Hindenach, Matthew J. Ellis, Yingwei Hu, Pei Wang, Daniel C. Rohrer, Sara R. Savage, Grace Zhao, Ludmila Danilova, Yige Wu, Parham Minoo, Jennifer M. Eschbacher, Nathan Edwards, T. Mamie Lih, Simina M. Boca, George D. Wilson, Alexey Shabunin, Bing Zhang, Michael A. Gillette, Brian J. Druker, David J. Clark, Jianbo Pan, Katarzyna Kusnierz, David Chesla, Ronald Matteotti, Corbin D. Jones, Michael J. Birrer, Lori J. Sokoll, Qing Kay Li, Mehdi Mesri, Peter B. McGarvey, Chet Birger, Barbara Pruetz, Daniel W. Chan, Bo Wen, Nicollette Maunganidze, and Jasmine Huang

Subjects
Adult, Male, Pancreatic ductal adenocarcinoma, Proteome, Gene Dosage, Biology, Adenocarcinoma, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Substrate Specificity, Cohort Studies, medicine, Humans, Molecular Targeted Therapy, Phosphorylation, Aged, Glycoproteins, Proteogenomics, Aged, 80 and over, MicroRNA sequencing, Genome, Human, RNA, Endothelial Cells, Methylation, Middle Aged, Phosphoproteins, Prognosis, Pancreatic Neoplasms, Phenotype, Cancer research, Female, KRAS, Signal transduction, Carcinogenesis, Transcriptome, Glycolysis, Protein Kinases, Algorithms, Carcinoma, Pancreatic Ductal
Abstract

Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.

Published
2021

3. Proteogenomic and metabolomic characterization of human glioblastoma

Author

Cristina E. Tognon, Larisa Polonskaya, Tara Skelly, Shuang Cai, Francesmary Modugno, Larissa Rossell, Nancy Roche, Chen Huang, Jessika Baral, Fulvio D'Angelo, Wen-Wei Liang, Chia-Feng Tsai, Sneha P. Couvillion, Karin D. Rodland, Jun Zhu, Liang-Bo Wang, Paul D. Piehowski, Antonio Colaprico, Anupriya Agarwal, Matthew A. Wyczalkowski, Umut Ozbek, Francesca Petralia, Alexis Demopoulos, William W. Maggio, Lin Chen, Katherine A. Hoadley, Richard D. Smith, Sandra Cottingham, John McGee, Marcin J. Domagalski, Houxiang Zhu, Emek Demir, Rebecca I. Montgomery, Jamie Moon, Rashna Madan, George D. Wilson, Luciano Garofano, Ewa P. Malc, Chelsea J. Newton, Steven A. Carr, Chandan Kumar-Sinha, Donghui Tan, Christopher R. Kinsinger, Oxana Paklina, Weiqing Wan, Stephanie De Young, Sandra Cerda, Shankha Satpathy, Wojciech Kaspera, Linda Hannick, Gad Getz, Runyu Hong, Shuangjia Lu, Ziad Hanhan, Daniel C. Rohrer, Annette Marrero-Oliveras, Wojciech Szopa, Yuxing Liao, Amanda G. Paulovich, Jiayi Ji, Denis A. Golbin, Tara Hiltke, Weiva Sieh, Piotr A. Mieczkowski, Matthew E. Monroe, Gilbert S. Omenn, Jill S. Barnholtz-Sloan, Azra Krek, Bing Zhang, Brittany Henderson, Peter B. McGarvey, Ratna R. Thangudu, Maciej Wiznerowicz, Saravana M. Dhanasekaran, Alex Webster, Kai Li, Karna Robinson, Nan Ji, Karl K. Weitz, Simina M. Boca, Xiaoyu Song, Anna Calinawan, Adam C. Resnick, Brian J. Druker, Dana R. Valley, David J. Clark, Tao Liu, Eric J. Jaehnig, Alicia Francis, Michele Ceccarelli, Rui Zhao, Dmitry Rykunov, Boris Reva, Elizabeth R. Duffy, Antonio Iavarone, Dave Tabor, Joshua F. McMichael, Daniel Cui Zhou, Maureen Dyer, Kimberly Elburn, Scott D. Jewell, Negin Vatanian, Shirley Tsang, Seungyeul Yoo, Alexander R. Pico, Grace Zhao, Kent J. Bloodsworth, Chet Birger, Jena Lilly, Eunkyung An, Jeffrey R. Whiteaker, Albert H. Kim, Yige Wu, Karen A. Ketchum, Felipe D. Leprevost, Alcida Karz, Uma Borate, Nathan Edwards, Uma Velvulou, Melissa Borucki, Vasileios Stathias, Sanford P. Markey, Corbin D. Jones, Ronald J. Moore, MacIntosh Cornwell, Karsten Krug, Michael J. Birrer, James Suh, Tomasz Czernicki, Jason E. McDermott, Emily S. Boja, Pei Wang, Nina Martinez, Wenke Liu, Yan Shi, Lili Blumenberg, Emily Kawaler, Jeffrey W. Tyner, Feng Chen, Jakub Stawicki, Ki Sung Um, Arul M. Chinnaiyan, Robert Zelt, Jacob J. Day, Zhen Zhang, Caleb M. Lindgren, Li Ding, Nikolay Gabrovski, Hongwei Liu, Jonathan T. Lei, Alla Karpova, Ramani B. Kothadia, Sailaja Mareedu, Mitual Amin, Hannah Boekweg, Jennifer E. Kyle, Sara R. Savage, Brian R. Rood, Yuriy Zakhartsev, Matthew L. Anderson, Alyssa Charamut, Wagma Caravan, Shakti Ramkissoon, Junmei Wang, Song Cao, Samuel H. Payne, Rosalie K. Chu, Rajiv Dhir, David W. Andrews, Galen Hostetter, Liqun Qi, Zhiao Shi, Milan G. Chheda, Robert Edwards, Hui Zhang, Weiping Ma, Jennifer M. Eschbacher, Stacey Gabriel, Jan Lubinski, Lijun Yao, Erika M. Zink, Kelly L. Stratton, William Bocik, Mathangi Thiagarajan, Shilpi Singh, Michael A. Gillette, Lisa M. Bramer, Thomas L. Bauer, Michael Vernon, Henry Rodriguez, Dimitris G. Placantonakis, Eric E. Schadt, Alexey I. Nesvizhskii, Vladislav A. Petyuk, Ana I. Robles, Yvonne Shutack, Anna Malovannaya, Stephen E. Stein, Xi Chen, Lyndon Kim, Yize Li, Shannon Richey, Stephan C. Schürer, Barbara Hindenach, Matthew J. Ellis, Yongchao Dou, David Fenyö, Amy M. Perou, Olga Potapova, Shrabanti Chowdhury, Andrew K. Godwin, Marcin Cieślik, Michael C. Wendl, Marina A. Gritsenko, Pietro Pugliese, Elie Traer, Simona Migliozzi, D. R. Mani, Houston Culpepper, Gregory J. Riggins, Xiaolu Yang, Mehdi Mesri, David Chesla, Lindsey K. Olsen, Lori J. Sokoll, Suhas Vasaikar, Liwei Zhang, Meghan C. Burke, Kelly V. Ruggles, Qing Kay Li, Daniel W. Chan, Bo Wen, Nicollette Maunganidze, Darlene Tansil, Joseph H. Rothstein, Barbara Pruetz, Pushpa Hariharan, Wang, L. -B., Karpova, A., Gritsenko, M. A., Kyle, J. E., Cao, S., Li, Y., Rykunov, D., Colaprico, A., Rothstein, J. H., Hong, R., Stathias, V., Cornwell, M., Petralia, F., Wu, Y., Reva, B., Krug, K., Pugliese, P., Kawaler, E., Olsen, L. K., Liang, W. -W., Song, X., Dou, Y., Wendl, M. C., Caravan, W., Liu, W., Cui Zhou, D., Ji, J., Tsai, C. -F., Petyuk, V. A., Moon, J., Ma, W., Chu, R. K., Weitz, K. K., Moore, R. J., Monroe, M. E., Zhao, R., Yang, X., Yoo, S., Krek, A., Demopoulos, A., Zhu, H., Wyczalkowski, M. A., Mcmichael, J. F., Henderson, B. L., Lindgren, C. M., Boekweg, H., Lu, S., Baral, J., Yao, L., Stratton, K. G., Bramer, L. M., Zink, E., Couvillion, S. P., Bloodsworth, K. J., Satpathy, S., Sieh, W., Boca, S. M., Schurer, S., Chen, F., Wiznerowicz, M., Ketchum, K. A., Boja, E. S., Kinsinger, C. R., Robles, A. I., Hiltke, T., Thiagarajan, M., Nesvizhskii, A. I., Zhang, B., Mani, D. R., Ceccarelli, M., Chen, X. S., Cottingham, S. L., Li, Q. K., Kim, A. H., Fenyo, D., Ruggles, K. V., Rodriguez, H., Mesri, M., Payne, S. H., Resnick, A. C., Wang, P., Smith, R. D., Iavarone, A., Chheda, M. G., Barnholtz-Sloan, J. S., Rodland, K. D., Liu, T., Ding, L., Agarwal, A., Amin, M., An, E., Anderson, M. L., Andrews, D. W., Bauer, T., Birger, C., Birrer, M. J., Blumenberg, L., Bocik, W. E., Borate, U., Borucki, M., Burke, M. C., Cai, S., Calinawan, A. P., Carr, S. A., Cerda, S., Chan, D. W., Charamut, A., Chen, L. S., Chesla, D., Chinnaiyan, A. M., Chowdhury, S., Cieslik, M. P., Clark, D. J., Culpepper, H., Czernicki, T., D'Angelo, F., Day, J., De Young, S., Demir, E., Dhanasekaran, S. M., Dhir, R., Domagalski, M. J., Druker, B., Duffy, E., Dyer, M., Edwards, N. J., Edwards, R., Elburn, K., Ellis, M. J., Eschbacher, J., Francis, A., Gabriel, S., Gabrovski, N., Garofano, L., Getz, G., Gillette, M. A., Godwin, A. K., Golbin, D., Hanhan, Z., Hannick, L. I., Hariharan, P., Hindenach, B., Hoadley, K. A., Hostetter, G., Huang, C., Jaehnig, E., Jewell, S. D., Ji, N., Jones, C. D., Karz, A., Kaspera, W., Kim, L., Kothadia, R. B., Kumar-Sinha, C., Lei, J., Leprevost, F. D., Li, K., Liao, Y., Lilly, J., Liu, H., Lubinski, J., Madan, R., Maggio, W., Malc, E., Malovannaya, A., Mareedu, S., Markey, S. P., Marrero-Oliveras, A., Martinez, N., Maunganidze, N., Mcdermott, J. E., Mcgarvey, P. B., Mcgee, J., Mieczkowski, P., Migliozzi, S., Modugno, F., Montgomery, R., Newton, C. J., Omenn, G. S., Ozbek, U., Paklina, O. V., Paulovich, A. G., Perou, A. M., Pico, A. R., Piehowski, P. D., Placantonakis, D. G., Polonskaya, L., Potapova, O., Pruetz, B., Qi, L., Ramkissoon, S., Resnick, A., Richey, S., Riggins, G., Robinson, K., Roche, N., Rohrer, D. C., Rood, B. R., Rossell, L., Savage, S. R., Schadt, E. E., Shi, Y., Shi, Z., Shutack, Y., Singh, S., Skelly, T., Sokoll, L. J., Stawicki, J., Stein, S. E., Suh, J., Szopa, W., Tabor, D., Tan, D., Tansil, D., Thangudu, R. R., Tognon, C., Traer, E., Tsang, S., Tyner, J., Um, K. S., Valley, D. R., Vasaikar, S., Vatanian, N., Velvulou, U., Vernon, M., Wan, W., Wang, J., Webster, A., Wen, B., Whiteaker, J. R., Wilson, G. D., Zakhartsev, Y., Zelt, R., Zhang, H., Zhang, L., Zhang, Z., Zhao, G., and Zhu, J.

Subjects
Proteomics, 0301 basic medicine, Cancer Research, CPTAC, Histone H2B acetylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Computational biology, Biology, Article, 03 medical and health sciences, lipidome, 0302 clinical medicine, Metabolomics, proteogenomic, Humans, Phosphorylation, EP300, proteomic, Proteogenomics, acetylome, single nuclei RNA-seq, Brain Neoplasms, Phospholipase C gamma, glioblastoma, Computational Biology, Lipidome, 030104 developmental biology, Histone, Oncology, Acetylation, 030220 oncology & carcinogenesis, Mutation, biology.protein, metabolome, signaling
Abstract

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. Wang et al. perform integrated proteogenomic analysis of adult glioblastoma (GBM), including metabolomics, lipidomics, and single nuclei RNA-Seq, revealing insights into the immune landscape of GBM, cell-specific nature of EMT signatures, histone acetylation in classical GBM, and the existence of signaling hubs which could provide therapeutic vulnerabilities.

Published
2021

4. A proteogenomic portrait of lung squamous cell carcinoma

Author

Shuang Cai, Elizabeth R. Duffy, Felipe da Veiga Leprevost, D. R. Mani, Antonio Colaprico, Jiayi Ji, Mehdi Mesri, Alicia Francis, Peter B. McGarvey, Myvizhi Esai Selvan, Corbin D. Jones, Michael J. Birrer, Robert J. Welsh, Lori Bernard, Shankha Satpathy, Li Ding, Sara R. Savage, Eugene S. Fedorov, Fernanda Martins Rodrigues, Marcin J. Domagalski, Jennifer M. Eschbacher, Shayan C. Avanessian, Boris Reva, Harsh Batra, Suhas Vasaikar, Nathan Edwards, Michael A. Gillette, Chet Birger, Scott D. Jewell, Kei Suzuki, William Bocik, Shilpi Singh, Meenakshi Anurag, Karen E. Christianson, Namrata D. Udeshi, Vasileios Stathias, Warren G. Tourtellotte, Karl R. Clauser, Shutack, Andrii Karnuta, Dana R. Valley, Kelly V. Ruggles, Qing Kay Li, Amanda G. Paulovich, MacIntosh Cornwell, Shankara Anand, Bartosz Kubisa, Pierre M. Jean Beltran, James Suh, Gilbert S. Omenn, Azra Krek, Wohaib Hasan, Yongchao Dou, David Fenyö, Henry Rodriguez, Samuel H. Payne, Małgorzata Wojtyś, Daniel W. Chan, Bo Wen, Nicollette Maunganidze, Özgün Babur, Renganayaki Pandurengan, Karen A. Ketchum, Nikolay Gabrovski, Pankaj Vats, Saravana M. Dhanasekaran, Richard D. Smith, Gad Getz, Sailaja Mareedu, Yuxing Liao, Mikhail Krotevich, Hui Zhang, Eric J. Jaehnig, Charles A. Goldthwaite, Alexey I. Nesvizhskii, Katherine A. Hoadley, Alexander A. Green, Francesca Petralia, Chandan Kumar-Sinha, Karsten Krug, Eunkyung An, Elena V. Ponomareva, Ximing Tang, Nancy Roche, Daniel C. Rohrer, David I. Heiman, Arul M. Chinnaiyan, Pamela Grady, Rebecca I. Montgomery, Galen Hostetter, Liqun Qi, Stephan C. Schürer, George D. Wilson, Pushpa Hariharan, Zhen Zhang, Yvonne, David Chesla, Chia-Kuei Mo, Maria Gabriela Raso, Negin Vatanian, Paul K. Paik, Fei Ding, Thomas L. Bauer, Barbara Hindenach, Matthew J. Ellis, Chen Huang, Karin D. Rodland, Oluwole Fadare, Ramaswamy Govindan, Eric E. Schadt, Sandra Cottingham, Barbara Pruetz, Sendurai A. Mani, Shirley Tsang, Carissa Huynh, Weiping Ma, Jennifer E. Maas, Tobias Schraink, Stacey Gabriel, Bing Zhang, Tara Hiltke, Rama Soundararajan, Tatiana Omelchenko, Brian J. Druker, Matthew A. Wyczalkowski, Neil R. Mucci, Ziad Hanhan, Donna E. Hansel, Yifat Geffen, Mathangi Thiagarajan, Xiaojun Jing, Pei Wang, Alfredo Molinolo, Tanmayi Vashist, Ratna R. Thangudu, Maciej Wiznerowicz, Edwin R. Parra, Tanvi H. Visal, Maureen Dyer, Melissa Borucki, Ki Sung Um, Jonathan T. Lei, Marcin Cieslik, Christopher R. Kinsinger, M. Harry Kane, Houxiang Zhu, Chelsea J. Newton, Steven A. Carr, Tao Liu, Wenke Liu, Volodymyr Sovenko, Olga Potapova, Eric J. Burks, Song Cao, Ana I. Robles, Yuping Zhang, Yize Li, Midie Xu, Erik J. Bergstrom, Zeynep H. Gümüş, Kai Li, and Xiaoyu Song

Subjects
Adult, Male, Epithelial-Mesenchymal Transition, Lung Neoplasms, Biology, Proteomics, Receptor Tyrosine Kinase-like Orphan Receptors, General Biochemistry, Genetics and Molecular Biology, Article, SOX2, CDKN2A, Survivin, medicine, Cluster Analysis, Humans, Receptors, Platelet-Derived Growth Factor, Phosphorylation, Lung cancer, Aged, Proteogenomics, Aged, 80 and over, EZH2, Ubiquitination, Cyclin-Dependent Kinase 4, Acetylation, Cyclin-Dependent Kinase 6, Middle Aged, medicine.disease, Chromatin, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Mutation, Cancer research, Carcinoma, Squamous Cell, Female, Protein Binding, Signal Transduction
Abstract

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

Published
2020

5. Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma

Author

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

Subjects
Adult, Male, Proteomics, 0301 basic medicine, Cancer Research, medicine.medical_treatment, Cell, Biology, Article, Young Adult, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Cyclin-dependent kinase, medicine, Humans, Aged, Proteogenomics, Aged, 80 and over, Squamous Cell Carcinoma of Head and Neck, Papillomavirus Infections, Phosphoproteomics, Immunotherapy, Middle Aged, medicine.disease, Head and neck squamous-cell carcinoma, Immune checkpoint, ErbB Receptors, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female
Abstract

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.

Published
2021
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6. Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma

Author

Yuxing Liao, Meghan C. Burke, Donghui Tan, Xiaoyu Song, Lauren C. Tang, Elizabeth R. Duffy, Shayan C. Avanessian, Daniel Cui Zhou, Maureen Dyer, Sara R. Savage, Jennifer M. Eschbacher, Shaleigh Smith, Alex Webster, Alicia Francis, Kelly V. Ruggles, Christopher R. Kinsinger, Shirley Tsang, Melissa Borucki, Nancy Roche, Pei Wang, Qing Kay Li, David Chesla, Ronald Matteotti, Zeynep H. Gümüş, Kai Li, Kei Suzuki, Thomas L. Bauer, Lori J. Sokoll, John McGee, Marcin J. Domagalski, Ki Sung Um, Tara Hiltke, Hai-Quan Chen, Hongwei Liu, Eric E. Schadt, Antonio Colaprico, Alyssa Charamut, Lijun Chen, Emily Kawaler, Ramani B. Kothadia, Mehdi Mesri, Jiayi Ji, Simina M. Boca, Myvizhi Esai Selvan, Emily S. Boja, Xi Chen, Shuang Cai, Kim Elburn, Samuel H. Payne, George D. Wilson, Peter B. McGarvey, Chelsea J. Newton, Felipe da Veiga Leprevost, Uma Velvulou, Tara Skelly, Corbin D. Jones, Michael J. Birrer, Steven A. Carr, Erik J. Bergstrom, Jeffrey R. Whiteaker, Michael H.A. Roehrl, Gad Getz, Tanya Krubit, Zhen Zhang, Yan Shi, Lili Blumenberg, Melanie A. MacMullan, Song Cao, Zhiao Shi, Weiping Ma, Chet Birger, Karl R. Clauser, Runyu Hong, Shankha Satpathy, Andrii Karnuta, Boris Reva, Barbara Hindenach, Matthew J. Ellis, Amanda G. Paulovich, Michael C. Wendl, Bing Zhang, Marina A. Gritsenko, Matthew A. Wyczalkowski, Stacey Gabriel, Michael A. Gillette, Jacob J. Day, Maciej Wiznerowicz, Stephen E. Stein, Ewa P. Malc, Robert J. Welsh, Sunita Shankar, Brian J. Druker, Li Ding, Lijun Yao, David J. Clark, Małgorzata Wojtyś, Dmitry Rykunov, Eugene S. Fedorov, Linda Hannick, Andrew K. Godwin, Sailaja Mareedu, Pushpa Hariharan, Mary Beth Beasley, Stephanie De Young, Arul M. Chinnaiyan, Robert Zelt, Mathangi Thiagarajan, Munziba Khan, Suhas Vasaikar, Tao Liu, Karin D. Rodland, Katherine A. Hoadley, Wen-Wei Liang, Ana I. Robles, Dana R. Valley, Sanford P. Markey, Mikhail Krotevich, David I. Heiman, Piotr A. Mieczkowski, Galen Hostetter, Liqun Qi, Yige Wu, Hui Zhang, Liang-Bo Wang, Nathan Edwards, Ramaswamy Govindan, Yifat Geffen, Seema Chugh, Alexey I. Nesvizhskii, Karen A. Ketchum, Pankaj Vats, Matthew E. Monroe, Marcin Cieslik, Yingwei Hu, Karsten Krug, Yosef E. Maruvka, Yize Li, Ratna R. Thangudu, William W. Maggio, Sandra Cottingham, Saravana M. Dhanasekaran, Wenke Liu, Hua Sun, Sonya Carter, Volodymyr Sovenko, M. Harry Kane, Annette Marrero-Oliveras, Barbara Pruetz, Amy M. Perou, Gilbert S. Omenn, Azra Krek, Olga Potapova, Michael S. Noble, Daniel W. Chan, Seungyeul Yoo, Eric J. Burks, Bo Wen, William Bocik, Michael Vernon, Henry Rodriguez, James Suh, Scott D. Jewell, MacIntosh Cornwell, Richard D. Smith, Chandan Kumar-Sinha, Halina M. Krzystek, Daniel C. Rohrer, Tatiana Omelchenko, D. R. Mani, Houston Culpepper, Vladislav A. Petyuk, Meng-Hong Sun, Michelle Chaikin, David Fenyö, Rahul Mannan, Bartosz Kubisa, Rohit Mehra, Rajwanth R. Veluswamy, Umut Ozbek, Michael Schnaubelt, Francesca Petralia, Elena V. Ponomareva, Rashna Madan, Pamela Grady, Karna Robinson, and Negin Vatanian

Subjects
0303 health sciences, Phosphoproteomics, Genomics, Environmental exposure, Computational biology, Biology, Proteomics, Proteogenomics, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Neutrophil degranulation, medicine, KRAS, 030217 neurology & neurosurgery, 030304 developmental biology, Epigenomics
Abstract

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.

Published
2020
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7. Proteogenomic Characterization of Endometrial Carcinoma

Author

David J. Clark, Jiayi Ji, Beom-Jun Kim, Doug W. Chan, Zhen Zhang, Kim Elburn, Munziba Khan, Katherine Fuh, Katherine A. Hoadley, Jeffrey R. Whiteaker, Peter B. McGarvey, Dana R. Valley, Douglas A. Levine, Sanford P. Markey, Hui Zhang, Tanya Krubit, Christopher R. Kinsinger, Hui Yin Chang, Yuxing Liao, Karen A. Ketchum, Piotr A. Mieczkowski, Pankaj Vats, Matthew E. Monroe, Donghui Tan, Alex Webster, Chet Birger, Kai Li, Ramani Kothadia, Saravana M. Dhanasekaran, Sara R. Savage, Karsten Krug, Marcin Jędryka, Matthew L. Anderson, Alyssa Charamut, Alexander R. Pico, Amanda G. Paulovich, Karna Robinson, Hua Zhou, John McGee, Sean J.I. Beecroft, Amanda E. Oliphant, Annette Marrero-Oliveras, Dmitry Rykunov, Shuang Cai, Francesmary Modugno, Marcin J. Domagalski, Emily Kawaler, Mehdi Mesri, Dmitry M. Avtonomov, Milan G. Chheda, Sue Hilsenbeck, Gilbert S. Omenn, Emek Demir, Rebecca I. Montgomery, Qingsong Gao, Azra Krek, Eric E. Schadt, Li Ding, George D. Wilson, Stephen E. Stein, David Chesla, Gad Getz, Negin Vatanian, Thomas F. Westbrook, Deborah DeLair, David I. Heiman, Karl R. Clauser, Rafal Matkowski, Lori J. Sokoll, Uma Borate, Antonio Colaprico, Jin Chen, Eric J. Jaehnig, Karin D. Rodland, Richard D. Smith, Linda Hannick, Uma Velvulou, Shannon Richey, Andrzej Czekański, Bing Zhang, Arul M. Chinnaiyan, Robert Zelt, Daniel J. Geiszler, Emily L. Hoskins, Ronald J. Moore, Pushpa Hariharan, Suhas Vasaikar, Jason E. McDermott, Yige Wu, Anna Malovannaya, Brian J. Druker, Jeffrey W. Tyner, Yan Shi, Lili Blumenberg, Jamie Moon, Cristina E. Tognon, Chandan Kumar-Sinha, Nathan Edwards, Yifat Geffen, Barbara Hindenach, Matthew J. Ellis, Zhi Li, Michael Schnaubelt, David C. Wheeler, Tara Skelly, Ewa P. Malc, Shrabanti Chowdhury, Andrew K. Godwin, Zhiao Shi, Francesca Petralia, Lin Chen, Scott D. Jewell, Daniel C. Rohrer, Elie Traer, Michael Ittmann, Shankha Satpathy, Marcin Cieslik, Weiping Ma, Daniel Cui Zhou, Maureen Dyer, Boris Reva, Rashna Madan, William Bocik, Stacey Gabriel, Stephanie De Young, Yosef E. Maruvka, Sandra Cottingham, Pamela Grady, D. R. Mani, Houston Culpepper, Meenakshi Anurag, Michael T. Lewis, Anupriya Agarwal, Felipe D. Leprevost, Jonathan C. Jarman, Michael Vernon, Henry Rodriguez, Matthew A. Wyczalkowski, Rui Zhao, Vladislav A. Petyuk, Michelle Chaikin, James Suh, Daniel W. Chan, Bo Wen, Patricia Castro, Alexey I. Nesvizhskii, Chia-Feng Tsai, Grace Zhao, Alicia Francis, Feng Chen, Mathangi Thiagarajan, Pei Wang, Marina A. Gritsenko, Anna Calinawan, David G. Mutch, Melissa Borucki, Xi Steven Chen, Guo Ci Teo, Peter Dottino, Corbin D. Jones, Michael J. Birrer, Ying Wang, Meghan C. Burke, MacIntosh Cornwell, Song Cao, Rosalie K. Chu, Larisa Polonskaya, Samuel H. Payne, Darlene Tansil, Yongchao Dou, David Fenyö, Kelly V. Ruggles, Qing Kay Li, Yuping Zhang, James J. Hsieh, Andy T. Kong, Ana I. Robles, Emily S. Boja, Chelsea J. Newton, Steven A. Carr, Sandra Cerda, Runyu Hong, Jacob J. Day, Sailaja Mareedu, Jan Lubinski, Galen Hostetter, Liqun Qi, Yize Li, Chen Huang, Liang-Bo Wang, Tao Liu, Renee Karabon, Paul D. Piehowski, Samuel L. Pugh, Maciej Wiznerowicz, Ratna R. Thangudu, Wenke Liu, Jayson B. Field, Sonya Carter, Ki Sung Um, Hongwei Liu, Alla Karpova, Yuriy Zakhartsev, Amy M. Perou, Michael S. Noble, Rajiv Dhir, Nancy Roche, Sunantha Sethuraman, Tara Hiltke, Lijun Chen, Xiaoyu Song, Elizabeth R. Duffy, Robert Edwards, Yingwei Hu, John A. Martignetti, Simina M. Boca, Michael A. Gillette, and David W Adams

Subjects
Epithelial-Mesenchymal Transition, Proteome, Druggability, Biology, Proteomics, Genomic Instability, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigens, Neoplasm, medicine, Animals, Humans, Phosphorylation, 030304 developmental biology, Feedback, Physiological, 0303 health sciences, Endometrial cancer, Carcinoma, Wnt signaling pathway, Cancer, Acetylation, medicine.disease, Proteogenomics, Endometrial Neoplasms, Gene Expression Regulation, Neoplastic, MicroRNAs, Serous fluid, Histone, Cancer research, biology.protein, Female, Transcriptome, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Microsatellite Repeats, Signal Transduction
Abstract

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.

Published
2020
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8. Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma

Author

David J. Clark, Jianbo Pan, Gerald W. Hart, Katherine A. Hoadley, Negin Vatanian, Shuang Cai, Yige Wu, Felipe da Veiga Leprevost, A. Ari Hakimi, Sanford P. Markey, Thomas F. Westbrook, Maciej Wiznerowicz, Nathan Edwards, Alla Y. Karpova, Sohini Sengupta, Marcin Cieslik, Samuel H. Payne, Xi Steven Chen, Guo Ci Teo, Jin Chen, Boris Reva, Corbin D. Jones, Michael J. Birrer, Ying Wang, Kelly V. Ruggles, Doug W. Chan, John McGee, Marcin J. Domagalski, Song Cao, Linda Hannick, Christopher R. Kinsinger, David I. Heiman, Jennifer M. Eschbacher, Munziba Khan, Jason E. McDermott, Dmitry M. Avtonomov, Sue Hilsenbeck, Qing Kay Li, Jiayi Ji, Emek Demir, Rebecca I. Montgomery, Qingsong Gao, Beom-Jun Kim, Xiaoyu Song, Karl R. Clauser, Christian P. Pavlovich, Richard D. Smith, Maureen Dyer, Jeffrey W. Tyner, Amy M. Perou, Yuping Zhang, Dana R. Valley, George D. Wilson, Shiyong Ma, Minghui Ao, Jiang Qian, Umut Ozbek, Melissa Borucki, Zhi Li, Michael Schnaubelt, Chen Huang, Piotr A. Mieczkowski, Francesca Petralia, Abdul Samad Hashimi, Hui Yin Chang, Liang-Bo Wang, Matthew E. Monroe, Peter B. McGarvey, Tao Liu, Karen A. Ketchum, Hui Zhang, Bing Zhang, D. R. Mani, Houston Culpepper, Hua Zhou, Saravana M. Dhanasekaran, Paul D. Piehowski, Zhidong Tu, Brian J. Druker, Ki Sung Um, Zhiao Shi, Uma Borate, Uma Velvulou, Michael Ittmann, Weiping Ma, Steven M. Foltz, Heng Zhu, Stacey Gabriel, Hongwei Liu, Ramani B. Kothadia, Lin Chen, Ewa P. Malc, Marina A. Gritsenko, Jun Zhu, David Chesla, Lori J. Sokoll, Stephen E. Stein, Andrzej Antczak, Matthew L. Anderson, Alyssa Charamut, Pamela Grady, Michael T. Lewis, Shannon Richey, Tanya Krubit, Alexander R. Pico, Kyung-Cho Cho, Daniel C. Rohrer, Francesmary Modugno, Stephanie De Young, Li Ding, Michael Smith, Mathangi Thiagarajan, Alexey I. Nesvizhskii, Shrabanti Chowdhury, Noam D. Beckmann, Kimberly R. Holloway, Ratna R. Thangudu, Sherri R. Davies, Tung-Shing M. Lih, Nicole Tignor, Anna Calinawan, Meghan C. Burke, Karna Robinson, Chet Birger, Shalin Patel, Antonio Colaprico, Sarah Keegan, Daniel J. Geiszler, Scott D. Jewell, William Bocik, Snehal Patil, Pei Wang, MacIntosh Cornwell, Emily Kawaler, Seungyeul Yoo, Jasmine Huang, Vladislav A. Petyuk, Ross Bremner, Donghui Tan, Stefani N. Thomas, Emily S. Boja, Anna Malovannaya, Xi Chen, Wenke Liu, Eric E. Schadt, Shankha Satpathy, Nancy Roche, Rajiv Dhir, Cristina E. Tognon, Michelle Chaikin, Gabriel Bromiński, Daniel C. Zhou, Yifat Geffen, Tara Skelly, Jacob J. Day, Sunantha Sethuraman, Sonya Carter, Zhen Zhang, Selim Kalayci, Michael Vernon, Zeynep H. Gümüş, Kai Li, Barbara Hindenach, Matthew J. Ellis, Meenakshi Anurag, David C. Wheeler, Sailaja Mareedu, Andy T. Kong, Arul M. Chinnaiyan, Robert Zelt, Annette Marrero-Oliveras, Henry Rodriguez, James Suh, Anupriya Agarwal, David Fenyö, Galen Hostetter, Liqun Qi, Matthew A. Wyczalkowski, W. Marston Linehan, Tara Hiltke, Feng Chen, Lijun Chen, Jan Lubinski, Chelsea J. Newton, Steven A. Carr, Tatiana Omelchenko, Gilbert S. Omenn, Karsten Krug, Ana I. Robles, Azra Krek, Runyu Hong, Milan G. Chheda, Yize Li, Yan Shi, Lili Blumenberg, Ruiyang Liu, Karin D. Rodland, Hua Sun, Kim Elburn, Jeffrey R. Whiteaker, Christopher J. Ricketts, Gaddy Getz, Daniel W. Chan, Bo Wen, Robert Edwards, Patricia Castro, Yingwei Hu, Pushpa Hariharan, Simina M. Boca, Darlene Tansil, Phillip M. Pierorazio, Yosef E. Maruvka, Sandra Cottingham, James J. Hsieh, Amanda G. Paulovich, Barbara Pruetz, Michael A. Gillette, Yihao Lu, Dmitry Rykunov, Mehdi Mesri, Marc M. Loriaux, Reyka G Jayasinghe, and Suhas Vasaikar

Subjects
Adult, Male, Cell, Computational biology, Biology, Proteomics, Disease-Free Survival, Oxidative Phosphorylation, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, medicine, Biomarkers, Tumor, Tumor Microenvironment, Humans, Exome, Phosphorylation, Carcinoma, Renal Cell, 030304 developmental biology, Epigenomics, Aged, Proteogenomics, Aged, 80 and over, 0303 health sciences, Tumor microenvironment, Genome, Human, Phosphoproteomics, Middle Aged, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Clear cell renal cell carcinoma, medicine.anatomical_structure, Female, 030217 neurology & neurosurgery, Signal Transduction
Abstract

SUMMARY To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale proteogenomic analysis of ccRCC to discern the functional impact of genomic alterations and provides evidence for rational treatment selection stemming from ccRCC pathobiology., Graphical Abstract, In Brief Comprehensive proteogenomic characterization in 103 treatment-naive clear cell renal cell carcinoma patient samples highlights tumor-specific alterations at the proteomic level that are unrevealed by transcriptomic profiling and proposes a revised subtyping scheme based on integrated omics analysis.

Published
2020
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