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Clin Cancer Res. 2013 May 1;19(9):2460-72. doi: 10.1158/1078-0432.CCR-12-3708. Epub 2013 Feb 26.

Tumor-specific isoform switch of the fibroblast growth factor receptor 2 underlies the mesenchymal and malignant phenotypes of clear cell renal cell carcinomas.

Author information

1
Ludwig Collaborative Laboratory, Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA.

Abstract

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.

PMID:
23444225
PMCID:
PMC3644028
DOI:
10.1158/1078-0432.CCR-12-3708
[Indexed for MEDLINE]
Free PMC Article

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