Insights of fibroblast growth factor receptor 3 aberrations in pan-cancer and their roles in potential clinical treatment

Fibroblast growth factor receptor 3 (FGFR3) alters frequently across various cancer types and is a common therapeutic target in bladder urothelial carcinoma (BLCA) with FGFR3 variants. Although emerging evidence supports the role of FGFR3 in individual cancer types, no pan-cancer analysis is available. In this work, we used the open comprehensive datasets, covering a total of 10,953 patients with 10,967 samples across 32 TCGA cancer types, to identify the full alteration spectrum of FGFR3. FGFR3 abnormal expression, methylation patterns, alteration frequency, mutation location distribution, functional impact, and prognostic implications differed greatly from cancer to cancer. The overall alteration frequency of FGFR3 was relatively low in all cancers. Targetable mutations were mainly detected in BLCA, and S249C, Y373C, G370C, and R248C were hotspot mutations that could be targeted by an FDA approved erdafitinib. Genetic fusions were mainly observed in glioma, followed by BLCA. FGFR3-TACC3 was the most common fusion type which was proposed as novel therapeutic targets in glioma and was targetable with erdafitinib in BLCA. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were two lung cancer subtypes, FGFR3 fusion and hotspot mutation like S249C were observed more commonly in LUSC but not in LUAD. DNA methylation was correlated with the expression of FGFR3 and its downstream genes in some tumors. FGFG3 abnormal expression and alterations exhibited clinical correlations with patient prognosis in several tumors. This work exhibited the full alteration spectrum of FGFR3 and indicated several new clues for their application as potential therapeutic targets and prognostic indicators.