title: Identification of molecular tumor markers in renal cell carcinomas with TFE3 protein expression by RNA sequencing.
abstract: TFE3 translocation renal cell carcinoma (tRCC) is defined by chromosomal translocations involving the TFE3 transcription factor at chromosome Xp11.2. Genetically proven TFE3 tRCCs have a broad histologic spectrum with overlapping features to other renal tumor subtypes. In this study, we aimed for characterizing RCC with TFE3 protein expression. Using next-generation whole transcriptome sequencing (RNA-Seq) as a discovery tool, we analyzed fusion transcripts, gene expression profile, and somatic mutations in frozen tissue of one TFE3 tRCC. By applying a computational analysis developed to call chimeric RNA molecules from paired-end RNA-Seq data, we confirmed the known TFE3 translocation. Its fusion partner SFPQ has already been described as fusion partner in tRCCs. In addition, an RNA read-through chimera between TMED6 and COG8 as well as MET and KDR (VEGFR2) point mutations were identified. An EGFR mutation, but no chromosomal rearrangements, was identified in a control group of five clear cell RCCs (ccRCCs). The TFE3 tRCC could be clearly distinguished from the ccRCCs by RNA-Seq gene expression measurements using a previously reported tRCC gene signature. In validation experiments using reverse transcription-PCR, TMED6-COG8 chimera expression was significantly higher in nine TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in 24 ccRCCs (P < .001) and 22 papillary RCCs (P < .05-.07). Immunohistochemical analysis of selected genes from the tRCC gene signature showed significantly higher eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) and Contactin 3 (CNTN3) expression in 16 TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in over 200 ccRCCs (P < .0001, both).
authors: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland ; Life Science Zurich PhD Program on Molecular and Translational Biomedicine, Zurich, Switzerland ; Competence Center for Systems Physiology and Metabolic Diseases, Zurich, Switzerland.
authors: Dorothee
authors: D
authors: Pflueger
authors: Andrea
authors: A
authors: Sboner
authors: Martina
authors: M
authors: Storz
authors: Jasmine
authors: J
authors: Roth
authors: Eva
authors: E
authors: Compérat
authors: Elisabeth
authors: E
authors: Bruder
authors: Mark A
authors: MA
authors: Rubin
authors: Peter
authors: P
authors: Schraml
authors: Holger
authors: H
authors: Moch
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D002648:Child; D058966:Contactins / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA / Q000379:methods; D014178:Translocation, Genetic; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; C484185:CNTN3 protein, human; C522290:COG8 protein, human; D058966:Contactins; C503234:EEF1A2 protein, human; D015514:Oncogene Proteins, Fusion; D020648:Peptide Elongation Factor 1; C069203:TFE3 protein, human; D033921:Vesicular Transport Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C000588866:KDR protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2