title: Next-generation sequencing of translocation renal cell carcinoma reveals novel RNA splicing partners and frequent mutations of chromatin-remodeling genes.
abstract: OBJECTIVE
  MITF/TFE translocation renal cell carcinoma (TRCC) is a rare subtype of kidney cancer. Its incidence and the genome-wide characterization of its genetic origin have not been fully elucidated.
  
  
  METHODS
  We performed RNA and exome sequencing on an exploratory set of TRCC (n = 7), and validated our findings using The Cancer Genome Atlas (TCGA) clear-cell RCC (ccRCC) dataset (n = 460).
  
  
  RESULTS
  Using the TCGA dataset, we identified seven TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of MITF/TFE (LUC7L3, KHSRP, and KHDRBS2) that are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared with other RCC types, and showed activation of MITF, the transforming growth factor β1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for MITF and ID2 targets. Exome sequencing of TRCC revealed a distinct mutational spectrum as compared with ccRCC, with frequent mutations in chromatin-remodeling genes (six of eight cases, three of which were from the TCGA). In two cases, we identified mutations in INO80D, an ATP-dependent chromatin-remodeling gene, previously shown to control the amplitude of the S phase. Knockdown of INO80D decreased cell proliferation in a novel cell line bearing LUC7L3-TFE3 translocation.
  
  
  CONCLUSIONS
  This genome-wide study defines the incidence of TRCC within a ccRCC-directed project and expands the genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing and frequent mutations in chromatin-remodeling genes.
authors.affiliation: Departments of Medical Oncology and ntannir@mdanderson.org gabriel.malouf@psl.aphp.fr.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Malouf
authors.affiliation: Bioinformatics and Computational Biology and.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.affiliation: Bioinformatics and Computational Biology and.
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.affiliation: Genitourinary Medical Oncology.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Gao
authors.affiliation: Genitourinary Medical Oncology.
authors.forename: Liangwen
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Genitourinary Medical Oncology.
authors.forename: Qiuming
authors.initials: Q
authors.lastname: He
authors.affiliation: Pathology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Faculty of Medicine Pierre et Marie Curie, Institut Universitaire de Cancérologie GRC5, University Paris 6;
authors.forename: Eva
authors.initials: E
authors.lastname: Compérat
authors.affiliation: Department of Genetics, Institut Curie;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Couturier
authors.affiliation: Department of Pathology, Hôpital Saint Joseph, Paris;
authors.forename: Vincent
authors.initials: V
authors.lastname: Molinié
authors.affiliation: Department of Medical Oncology, Institut Gustave Roussy, Villejuif;
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.affiliation: Centre de Pathologie, Amiens, Picardie, France; Departments of.
authors.forename: Philippe
authors.initials: P
authors.lastname: Camparo
authors.affiliation: DNA Analysis Facility, Department of Genetics.
authors.forename: Denaha J
authors.initials: DJ
authors.lastname: Doss
authors.affiliation: DNA Analysis Facility, Department of Genetics.
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Thompson
authors.affiliation: Departments of Medical Oncology and.
authors.forename: David
authors.initials: D
authors.lastname: Khayat
authors.affiliation: Division of Surgery, Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Willie
authors.initials: W
authors.lastname: Yu
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Bioinformatics and Computational Biology and.
authors.forename: John
authors.initials: J
authors.lastname: Weinstein
authors.affiliation: Genitourinary Medical Oncology, ntannir@mdanderson.org gabriel.malouf@psl.aphp.fr.
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D009687:Nuclear Proteins; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C485572:KHDRBS2 protein, human; C105789:KHSRP protein, human; C404083:LUC7L3 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C524421:INO80 protein, human