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

  1. Author:
    Li, Yize
    Lih, Tung-Shing M
    Dhanasekaran, Saravana M
    Mannan, Rahul
    Chen, Lijun
    Cieslik, Marcin
    Wu, Yige
    Lu, Rita Jiu-Hsien
    Clark, David J
    Kolodziejczak, Iga
    Hong, Runyu
    Chen, Siqi
    Zhao, Yanyan
    Chugh, Seema
    Caravan, Wagma
    Naser Al Deen, Nataly
    Hosseini, Noshad
    Newton, Chelsea J
    Krug, Karsten
    Xu, Yuanwei
    Cho, Kyung-Cho
    Hu, Yingwei
    Zhang, Yuping
    Kumar-Sinha, Chandan
    Ma, Weiping
    Calinawan, Anna
    Wyczalkowski, Matthew A
    Wendl, Michael C
    Wang, Yuefan
    Guo, Shenghao
    Zhang, Cissy
    Le, Anne
    Dagar, Aniket
    Hopkins, Alex
    Cho, Hanbyul
    Leprevost, Felipe da Veiga
    Jing, Xiaojun
    Teo, Guo Ci
    Liu, Wenke
    Reimers, Melissa A
    Pachynski, Russell
    Lazar, Alexander J
    Chinnaiyan, Arul M
    Van Tine, Brian A
    Zhang, Bing
    Rodland, Karin D
    Getz, Gad
    Mani, D R
    Wang, Pei
    Chen, Feng
    Hostetter, Galen
    Thiagarajan,Mathangi
    Linehan, W Marston
    Fenyö, David
    Jewell, Scott D
    Omenn, Gilbert S
    Mehra, Rohit
    Wiznerowicz, Maciej
    Robles, Ana I
    Mesri, Mehdi
    Hiltke, Tara
    An, Eunkyung
    Rodriguez, Henry
    Chan, Daniel W
    Ricketts, Christopher J
    Nesvizhskii, Alexey I
    Zhang, Hui
    Ding, Li

  2. Author Address

    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 Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21213, USA., 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., 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., International Institute for Molecular Oncology, 60-203 Poznan, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland., 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., Van Andel Research Institute, Grand Rapids, MI 49503, USA., Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA., Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA., Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, 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; Department of Mathematics, Washington University in St. Louis, St. Louis, MO 63130, USA., Department of Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA., 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 Pathology, University of Michigan, Ann Arbor, MI 48109, USA., 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., Departments of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., 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., Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA., Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA., 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., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, 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; Department of Internal Medicine, Human Genetics, and School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA., International Institute for Molecular Oncology, 60-203 Poznan, Poland; Heliodor Swiecicki Clinical Hospital in Poznan, ul. Przybyszewskiego 49, 60-355 Poznan, Poland; Poznan University of Medical Sciences, 61-701 Poznan, Poland., Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, USA., 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., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: chris.ricketts@nih.gov., 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., 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.,
    1. Year: 2023
    2. Date: Jan 9
    3. Epub Date: 2022 12 20
  2. Journal: Cancer Cell
    1. 41
    2. 1
    3. Pages: 139-163
  4. Type of Article: Article
  1. 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. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.ccell.2022.12.001
  3. PMID: 36563681
  4. View record in Web of Science®
  5. WOS: 000925383000001
  6. PII : S1535-6108(22)00565-7

Library Notes

  1. Fiscal Year: FY2022-2023
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