Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness PMID: 36563681

ADC Targets in Oncology

2026-04-10

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

Cancer Cell. 2022 Dec 20;S1535-6108(22)00565-7. doi: 10.1016/j.ccell.2022.12.001.

Yize Li ¹ , Tung-Shing M Lih ² , Saravana M Dhanasekaran ³ , Rahul Mannan ⁴ , Lijun Chen ² , Marcin Cieslik ⁵ , Yige Wu ¹ , Rita Jiu-Hsien Lu ¹ , David J Clark ² , Iga Kołodziejczak ⁶ , Runyu Hong ⁷ , Siqi Chen ¹ , Yanyan Zhao ¹ , Seema Chugh ⁴ , Wagma Caravan ¹ , Nataly Naser Al Deen ¹ , Noshad Hosseini ⁵ , Chelsea J Newton ⁸ , Karsten Krug ⁹ , Yuanwei Xu ¹⁰ , Kyung-Cho Cho ² , Yingwei Hu ² , Yuping Zhang ⁴ , Chandan Kumar-Sinha ⁴ , Weiping Ma ¹¹ , Anna Calinawan ¹¹ , Matthew A Wyczalkowski ¹ , Michael C Wendl ¹² , Yuefan Wang ² , Shenghao Guo ¹³ , Cissy Zhang ² , Anne Le ¹⁴ , Aniket Dagar ⁴ , Alex Hopkins ⁴ , Hanbyul Cho ⁵ , Felipe da Veiga Leprevost ¹⁵ , Xiaojun Jing ⁴ , Guo Ci Teo ⁴ , Wenke Liu ⁷ , Melissa A Reimers ¹⁶ , Russell Pachynski ¹⁶ , Alexander J Lazar ¹⁷ , Arul M Chinnaiyan ⁵ , Brian A Van Tine ¹⁸ , Bing Zhang ¹⁹ , Karin D Rodland ²⁰ , Gad Getz ⁹ , D R Mani ⁹ , Pei Wang ¹¹ , Feng Chen ²¹ , Galen Hostetter ⁸ , Mathangi Thiagarajan ²² , W Marston Linehan ²³ , David Fenyö ⁷ , Scott D Jewell ⁸ , Gilbert S Omenn ²⁴ , Rohit Mehra ⁴ , Maciej Wiznerowicz ²⁵ , Ana I Robles ²⁶ , Mehdi Mesri ²⁶ , Tara Hiltke ²⁶ , Eunkyung An ²⁶ , Henry Rodriguez ²⁶ , Daniel W Chan ²⁷ , Christopher J Ricketts ²⁸ , Alexey I Nesvizhskii ⁵ , Hui Zhang ²⁹ , Li Ding ³⁰ , Clinical Proteomic Tumor Analysis Consortium

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: [email protected].
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: [email protected].
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: [email protected].
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: [email protected].

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.