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Cell Rep. 2016 Mar 15;14(10):2476-89. doi: 10.1016/j.celrep.2016.02.024. Epub 2016 Mar 3.

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.

Author information

1
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
2
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland.
4
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Urology, Yale School of Medicine, New Haven, CT 06520, USA.
6
Department of Dermatology, Yale University, New Haven, CT 06510, USA; Department of Pathology, Yale University, New Haven, CT 06510, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
8
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
9
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
10
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
11
Department of Convergence Technology Research, Korea Institute of Science and Technology Information (KAIST), Daejeon 305-806, Korea.
12
Department of Convergence Technology Research, Korea Institute of Science and Technology Information (KAIST), Daejeon 305-806, Korea; Department of Bio and Brain Engineering, KAIST, Daejeon 305-806, Korea.
13
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
14
Department of Pathology, Memorial Sloan-Kettering Cancer, New York, NY 10065, USA.
15
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA.
16
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
17
Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
18
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
19
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
20
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
21
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
22
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
23
Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
24
Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA.
25
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
26
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
27
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
28
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: creighto@bcm.edu.

Abstract

On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.

PMID:
26947078
PMCID:
PMC4794376
DOI:
10.1016/j.celrep.2016.02.024
[Indexed for MEDLINE]
Free PMC Article

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