American Association for Cancer Research
10780432ccr123708-sup-tab3.xlsx (12.25 kB)

Supplementary Table 3 from Tumor-Specific Isoform Switch of the Fibroblast Growth Factor Receptor 2 Underlies the Mesenchymal and Malignant Phenotypes of Clear Cell Renal Cell Carcinomas

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posted on 2023-03-31, 17:24 authored by Qi Zhao, Otavia L. Caballero, Ian D. Davis, Eric Jonasch, Pheroze Tamboli, W.K. Alfred Yung, John N. Weinstein, Robert L. Strausberg, Jun Yao

XLSX file - 12K, Predicted percentages of samples having FGFR2 IIIc as the major isoform in multiple cancers



Purpose: We aim to identify tumor-specific alternative splicing events having potential applications in the early detection, diagnosis, prognosis, and therapy for cancers.Experimental Design: 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. Clin Cancer Res; 19(9); 2460–72. ©2013 AACR.