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

Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma.

Author information

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

PMID:
31675502
DOI:
10.1016/j.cell.2019.10.007
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