title: Tumor-specific isoform switch of the fibroblast growth factor receptor 2 underlies the mesenchymal and malignant phenotypes of clear cell renal cell carcinomas.
abstract: OBJECTIVE
  We aim to identify tumor-specific alternative splicing events having potential applications in the early detection, diagnosis, prognosis, and therapy for cancers.
  
  
  METHODS
  We analyzed RNA-seq data on 470 clear cell renal cell carcinomas (ccRCC) and 68 kidney tissues to identify tumor-specific alternative splicing events. We further focused on the fibroblast growth factor receptor 2 (FGFR2) isoform switch and characterized ccRCCs expressing different FGFR2 isoforms by integrated analyses using genomic data from multiple platforms and tumor types.
  
  
  RESULTS
  We identified 113 top candidate alternatively spliced genes in ccRCC. Prominently, the FGFR2 gene transcript switched from the normal IIIb isoform ("epithelial") to IIIc isoform ("mesenchymal") in nearly 90% of ccRCCs. This switch is kidney specific as it was rarely observed in other cancers. The FGFR2-IIIb ccRCCs show a transcriptome and methylome resembling those from normal kidney, whereas FGFR2-IIIc ccRCCs possess elevated hypoxic and mesenchymal expression signatures. Clinically, FGFR2-IIIb ccRCCs are smaller in size, of lower tumor grade, and associated with longer patient survival. Gene set enrichment and DNA copy number analyses indicated that FGFR2-IIIb ccRCCs are closely associated with renal oncocytomas and chromophobe RCCs (chRCC). A reexamination of tumor histology by pathologists identified FGFR2-IIIb tumors as chRCCs and clear cell papillary RCCs (ccpRCC).
  
  
  CONCLUSIONS
  FGFR2 IIIb RCCs represent misdiagnosed ccRCC cases, suggesting FGFR2 isoform testing can be used in the diagnosis of RCC subtypes. The finding of a prevalent isoform switch of FGFR2 in a tissue-specific manner holds promise for the future development of FGFR2-IIIc as a distinct early detection biomarker and therapeutic target for ccRCC.
authors: Ludwig Collaborative Laboratory, Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Qi
authors: Q
authors: Zhao
authors: Otavia L
authors: OL
authors: Caballero
authors: Ian D
authors: ID
authors: Davis
authors: Eric
authors: E
authors: Jonasch
authors: Pheroze
authors: P
authors: Tamboli
authors: W K Alfred
authors: WK
authors: Yung
authors: John N
authors: JN
authors: Weinstein
authors: Robert L
authors: RL
authors: Strausberg
authors: Jun
authors: J
authors: Yao
mesh_terms: D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D016000:Cluster Analysis; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009928:Organ Specificity; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C539364:ESRP1 protein, human; C470830:GRHL2 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2