Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma

David J Clark; Saravana M Dhanasekaran; Francesca Petralia; Jianbo Pan; Xiaoyu Song; Yingwei Hu; Felipe da Veiga Leprevost; Boris Reva; Tung-Shing M Lih; Hui-Yin Chang; Weiping Ma; Chen Huang; Christopher J Ricketts; Lijun Chen; Azra Krek; Yize Li; Dmitry Rykunov; Qing Kay Li; Lin S Chen; Umut Ozbek; Suhas Vasaikar; Yige Wu; Seungyeul Yoo; Shrabanti Chowdhury; Matthew A Wyczalkowski; Jiayi Ji; Michael Schnaubelt; Andy Kong; Sunantha Sethuraman; Dmitry M Avtonomov; Minghui Ao; Antonio Colaprico; Song Cao; Kyung-Cho Cho; Selim Kalayci; Shiyong Ma; Wenke Liu; Kelly Ruggles; Anna Calinawan; Zeynep H Gümüş; Daniel Geiszler; Emily Kawaler; Guo Ci Teo; Bo Wen; Yuping Zhang; Sarah Keegan; Kai Li; Feng Chen; Nathan Edwards; Phillip M Pierorazio; Xi Steven Chen; Christian P Pavlovich; A Ari Hakimi; Gabriel Brominski; James J Hsieh; Andrzej Antczak; Tatiana Omelchenko; Jan Lubinski; Maciej Wiznerowicz; W Marston Linehan; Christopher R Kinsinger; Mathangi Thiagarajan; Emily S Boja; Mehdi Mesri; Tara Hiltke; Ana I Robles; Henry Rodriguez; Jiang Qian; David Fenyö; Bing Zhang; Li Ding; Eric Schadt; Arul M Chinnaiyan; Zhen Zhang; Gilbert S Omenn; Marcin Cieslik; Daniel W Chan; Alexey I Nesvizhskii; Pei Wang; Hui Zhang; Clinical Proteomic Tumor Analysis Consortium

doi:10.1016/j.cell.2019.10.007

Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma

Cell. 2019 Oct 31;179(4):964-983.e31. doi: 10.1016/j.cell.2019.10.007.

Authors

David J Clark¹, Saravana M Dhanasekaran², Francesca Petralia³, Jianbo Pan¹, Xiaoyu Song⁴, Yingwei Hu¹, Felipe da Veiga Leprevost², Boris Reva³, Tung-Shing M Lih¹, Hui-Yin Chang², Weiping Ma³, Chen Huang⁵, Christopher J Ricketts⁶, Lijun Chen¹, Azra Krek³, Yize Li⁷, Dmitry Rykunov³, Qing Kay Li¹, Lin S Chen⁸, Umut Ozbek⁴, Suhas Vasaikar⁹, Yige Wu⁷, Seungyeul Yoo³, Shrabanti Chowdhury³, Matthew A Wyczalkowski⁷, Jiayi Ji⁴, Michael Schnaubelt¹, Andy Kong², Sunantha Sethuraman⁷, Dmitry M Avtonomov², Minghui Ao¹, Antonio Colaprico¹⁰, Song Cao⁷, Kyung-Cho Cho¹, Selim Kalayci³, Shiyong Ma¹, Wenke Liu¹¹, Kelly Ruggles¹², Anna Calinawan³, Zeynep H Gümüş³, Daniel Geiszler¹³, Emily Kawaler¹¹, Guo Ci Teo², Bo Wen⁵, Yuping Zhang², Sarah Keegan¹¹, Kai Li⁵, Feng Chen¹⁴, Nathan Edwards¹⁵, Phillip M Pierorazio¹⁶, Xi Steven Chen¹⁷, Christian P Pavlovich¹⁶, A Ari Hakimi¹⁸, Gabriel Brominski¹⁹, James J Hsieh²⁰, Andrzej Antczak¹⁹, Tatiana Omelchenko²¹, Jan Lubinski²², Maciej Wiznerowicz²³, W Marston Linehan⁶, Christopher R Kinsinger²⁴, Mathangi Thiagarajan²⁵, Emily S Boja²⁴, Mehdi Mesri²⁴, Tara Hiltke²⁴, Ana I Robles²⁴, Henry Rodriguez²⁴, Jiang Qian²⁶, David Fenyö¹¹, Bing Zhang²⁷, Li Ding⁷, Eric Schadt²⁸, Arul M Chinnaiyan², Zhen Zhang¹, Gilbert S Omenn²⁹, Marcin Cieslik³⁰, Daniel W Chan³¹, Alexey I Nesvizhskii³², Pei Wang³³, Hui Zhang³⁴; Clinical Proteomic Tumor Analysis Consortium

Collaborators

Clinical Proteomic Tumor Analysis Consortium:
Abdul Samad Hashimi, Alexander R Pico, Alla Karpova, Alyssa Charamut, Amanda G Paulovich, Amy M Perou, Anna Malovannaya, Annette Marrero-Oliveras, Anupriya Agarwal, Barbara Hindenach, Barbara Pruetz, Beom-Jun Kim, Brian J Druker, Chelsea J Newton, Chet Birger, Corbin D Jones, Cristina Tognon, D R Mani, Dana R Valley, Daniel C Rohrer, Daniel C Zhou, Darlene Tansil, David Chesla, David Heiman, David Wheeler, Donghui Tan, Doug Chan, Emek Demir, Ewa Malc, Francesmary Modugno, Gaddy Getz, Galen Hostetter, George D Wilson, Gerald W Hart, Heng Zhu, Hongwei Liu, Houston Culpepper, Hua Sun, Hua Zhou, Jacob Day, James Suh, Jasmine Huang, Jason McDermott, Jeffrey R Whiteaker, Jeffrey W Tyner, Jennifer Eschbacher, Jin Chen, John McGee, Jun Zhu, Karen A Ketchum, Karin D Rodland, Karl Clauser, Karna Robinson, Karsten Krug, Katherine A Hoadley, Ki Sung Um, Kim Elburn, Kimberly Holloway, Liang-Bo Wang, Lili Blumenberg, Linda Hannick, Liqun Qi, Lori J Sokoll, MacIntosh Cornwell, Marc Loriaux, Marcin J Domagalski, Marina A Gritsenko, Matthew Anderson, Matthew E Monroe, Matthew J Ellis, Maureen Dyer, Meenakshi Anurag, Meghan C Burke, Melissa Borucki, Michael A Gillette, Michael J Birrer, Michael Lewis, Michael M Ittmann, Michael Smith, Michael Vernon, Michelle Chaikin, Milan G Chheda, Munziba Khan, Nancy Roche, Nathan J Edwards, Negin Vatanian, Nicole Tignor, Noam Beckmann, Pamela Grady, Patricia Castro, Paul Piehowski, Peter B McGarvey, Piotr Mieczkowski, Pushpa Hariharan, Qingsong Gao, Rajiv Dhir, Ramani Bhupendra Kothadia, Ratna R Thangudu, Rebecca Montgomery, Reyka G Jayasinghe, Richard D Smith, Robert Edwards, Robert Zelt, Ross Bremner, Ruiyang Liu, Runyu Hong, Sailaja Mareedu, Samuel H Payne, Sandra Cottingham, Sanford P Markey, Scott D Jewell, Shalin Patel, Shankha Satpathy, Shannon Richey, Sherri R Davies, Shuang Cai, Simina M Boca, Snehal Patil, Sohini Sengupta, Sonya Carter, Stacey Gabriel, Stefani N Thomas, Stephanie De Young, Stephen E Stein, Steven A Carr, Steven M Foltz, Sue Hilsenbeck, Tanya Krubit, Tao Liu, Tara Skelly, Thomas Westbrook, Uma Borate, Uma Velvulou, Vladislav A Petyuk, William E Bocik, Xi Chen, Yan Shi, Yifat Geffen, Yihao Lu, Ying Wang, Yosef Maruvka, Zhi Li, Zhiao Shi, Zhidong Tu

Affiliations

¹ Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA.
² Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Washington University School of Medicine, St. Louis, MO 63110, USA.
⁸ Department of Public Health Sciences, University of Chicago, Chicago, IL 60637, USA.
⁹ Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
¹¹ Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
¹² Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
¹³ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁴ Departments of Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁵ Department of Biochemistry and Cellular Biology, Georgetown University, Washington, DC 20007, USA.
¹⁶ Brady Urological Institute and Department of Urology, Johns Hopkins University, Baltimore, MD 21231, USA.
¹⁷ Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
¹⁸ Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁹ Department of Urology, Poznań University of Medical Sciences, Szwajcarska 3, Poznań 61-285, Poland.
²⁰ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
²¹ Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²² Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 71-252, Poland.
²³ International Institute for Molecular Oncology, Poznań 60-203, Poland; Poznań University of Medical Sciences, Poznan 60-701, Poland.
²⁴ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA.
²⁵ Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
²⁶ Department of Ophthalmology, Johns Hopkins University, Baltimore, MD 21231, USA.
²⁷ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
²⁸ Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Sema4, Stamford, CT 06902, USA.
²⁹ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Human Genetics, and School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
³⁰ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: mcieslik@med.mich.edu.
³¹ Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address: dchan@jhmi.edu.
³² Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: nesvi@med.umich.edu.
³³ Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: pei.wang@mssm.edu.
³⁴ Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address: huizhang@jhu.edu.

Abstract

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.

Keywords: CPTAC; ccRCC; chromosomal translocation; drug targets; immune infiltration; phosphoproteomics; proteogenomics; proteomics; renal carcinoma; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor / genetics
Biomarkers, Tumor / immunology
Carcinoma, Renal Cell / genetics*
Carcinoma, Renal Cell / immunology
Carcinoma, Renal Cell / pathology
Disease-Free Survival
Exome / genetics
Exome Sequencing
Female
Gene Expression Regulation, Neoplastic / genetics
Genome, Human / genetics
Humans
Male
Middle Aged
Neoplasm Proteins / genetics*
Neoplasm Proteins / immunology
Oxidative Phosphorylation
Phosphorylation / genetics
Proteogenomics*
Signal Transduction / genetics
Transcriptome / genetics*
Transcriptome / immunology
Tumor Microenvironment / genetics
Tumor Microenvironment / immunology

Substances

Biomarkers, Tumor
Neoplasm Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding