title: Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.
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.
authors.affiliation: Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Fengju
authors.initials: F
authors.lastname: Chen
authors.affiliation: Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Şenbabaoğlu
authors.affiliation: Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciriello
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lixing
authors.initials: L
authors.lastname: Yang
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ed
authors.initials: E
authors.lastname: Reznik
authors.affiliation: Department of Urology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Shuch
authors.affiliation: Department of Dermatology, Yale University, New Haven, CT 06510, USA; Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Goran
authors.initials: G
authors.lastname: Micevic
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: De Velasco
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Eve
authors.initials: E
authors.lastname: Shinbrot
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Noble
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Xi
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Drummond
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Department of Convergence Technology Research, Korea Institute of Science and Technology Information (KAIST), Daejeon 305-806, Korea.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Junehawk
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Pheroze
authors.initials: P
authors.lastname: Tamboli
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer, New York, NY 10065, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Reuter
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA.
authors.forename: Carl Simon
authors.initials: CS
authors.lastname: Shelley
authors.affiliation: 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.
authors.forename: Benny A
authors.initials: BA
authors.lastname: Kaipparettu
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Bottaro
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: 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.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: 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.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Henske
authors.affiliation: Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rehan
authors.initials: R
authors.lastname: Akbani
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: 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.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D002843:Chromatin / Q000378:metabolism; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D035683:MicroRNAs / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002843:Chromatin; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; C069203:TFE3 protein, human