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

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; Clinical Proteomic Tumor Analysis Consortium

doi:10.1016/j.ccell.2022.12.001

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

Cancer Cell. 2023 Jan 9;41(1):139-163.e17. doi: 10.1016/j.ccell.2022.12.001. Epub 2022 Dec 22.

Authors

Yize Li¹, Tung-Shing M Lih², Saravana M Dhanasekaran³, Rahul Mannan⁴, Lijun Chen², Marcin Cieslik⁵, Yige Wu¹, Rita Jiu-Hsien Lu¹, David J Clark², Iga Kołodziejczak⁶, Runyu Hong⁷, Siqi Chen¹, Yanyan Zhao¹, Seema Chugh⁴, Wagma Caravan¹, Nataly Naser Al Deen¹, Noshad Hosseini⁵, Chelsea J Newton⁸, Karsten Krug⁹, Yuanwei Xu¹⁰, Kyung-Cho Cho², Yingwei Hu², Yuping Zhang⁴, Chandan Kumar-Sinha⁴, Weiping Ma¹¹, Anna Calinawan¹¹, Matthew A Wyczalkowski¹, Michael C Wendl¹², Yuefan Wang², Shenghao Guo¹³, Cissy Zhang², Anne Le¹⁴, Aniket Dagar⁴, Alex Hopkins⁴, Hanbyul Cho⁵, Felipe da Veiga Leprevost¹⁵, Xiaojun Jing⁴, Guo Ci Teo⁴, Wenke Liu⁷, Melissa A Reimers¹⁶, Russell Pachynski¹⁶, Alexander J Lazar¹⁷, Arul M Chinnaiyan⁵, Brian A Van Tine¹⁸, Bing Zhang¹⁹, Karin D Rodland²⁰, Gad Getz⁹, D R Mani⁹, Pei Wang¹¹, Feng Chen²¹, Galen Hostetter⁸, Mathangi Thiagarajan²², W Marston Linehan²³, David Fenyö⁷, Scott D Jewell⁸, Gilbert S Omenn²⁴, Rohit Mehra⁴, Maciej Wiznerowicz²⁵, Ana I Robles²⁶, Mehdi Mesri²⁶, Tara Hiltke²⁶, Eunkyung An²⁶, Henry Rodriguez²⁶, Daniel W Chan²⁷, Christopher J Ricketts²⁸, Alexey I Nesvizhskii⁵, Hui Zhang²⁹, Li Ding³⁰; Clinical Proteomic Tumor Analysis Consortium

Collaborators

Clinical Proteomic Tumor Analysis Consortium:
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 Jr, 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, Zhen Zhang

Affiliations

¹ Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.
² Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA.
³ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: saravana@med.umich.edu.
⁴ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ International Institute for Molecular Oncology, 60-203 Poznań, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland.
⁷ Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁸ Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
¹⁰ Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA.
¹¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
¹² McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Mathematics, Washington University in St. Louis, St. Louis, MO 63130, USA.
¹³ Department of Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA.
¹⁴ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁵ Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁶ Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA; Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
¹⁷ Departments of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁸ Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA.
¹⁹ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
²⁰ Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
²¹ Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO 63130, USA.
²² Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
²³ Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
²⁴ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; 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.
²⁵ International Institute for Molecular Oncology, 60-203 Poznań, Poland; Heliodor Swiecicki Clinical Hospital in Poznań, ul. Przybyszewskiego 49, 60-355 Poznań, Poland; Poznań University of Medical Sciences, 61-701 Poznań, Poland.
²⁶ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA.
²⁷ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁸ Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: chris.ricketts@nih.gov.
²⁹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: huizhang@jhu.edu.
³⁰ Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63130, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA. Electronic address: lding@wustl.edu.

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.

Keywords: CPTAC; UCHL1; clear cell renal cell carcinoma; glycoproteomics; histology; metabolome; phosphoproteomics; proteogenomics; single-nuclei RNA-seq; tumor heterogeneity.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Biomarkers, Tumor / genetics
Carcinoma, Renal Cell* / genetics
Carcinoma, Renal Cell* / pathology
Humans
Kidney Neoplasms* / genetics
Kidney Neoplasms* / pathology
Prognosis
Proteogenomics*
Treatment Outcome

Substances

Biomarkers, Tumor

Abstract

Publication types

MeSH terms

Substances

Grants and funding