Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer

Abstract

In addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical significance it may possess with regard to BC. The present study aimed to investigate the immunoreactivity of FGFR3 in primary urothelial bladder tumours, with regard to clinicopathological features and FGFR3 mutation status. Tissue microarrays were used to immunohistochemically analyse FGFR3 expression in 255 primary, unselected patients with BC. FGFR3 mutations were detected using SNaPshot analysis. Positive FGFR3 immunoreactivity was identified in 113/207 analysable cases (54.6%), and was significantly associated with FGFR3 mutation (P<0.001), low tumour stage (P<0.001), low histological grade (P<0.001) and a papillary growth pattern (P<0.001). Positive FGFR3 immunostaining (P=0.002) and FGFR3 mutation (P=0.002) were found to be significantly associated with increased disease-specific survival following univariate analysis, demonstrating a median follow-up period of 75 months. Using multivariate analyses, FGFR3 immunoreactivity was found not to be independent of classical pathological parameters. Immunohistochemical expression of FGFR3 is an early occurrence during the carcinogenesis of papillary non-invasive BC. The presence of FGFR3 immunoreactivity in non-invasive papillary urothelial carcinomas may be utilised as an indicator of tumours possessing low-grade features and good prognosis.

Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer

“…mRNA overexpression but not mutations or protein expression were also associated with favorable prognosis. In the literature, immunohistochemical data show protein overexpression also related to good prognosis 18 . In our series, there was a good correlation between mRNA expression and DNA mutation.…”

“…In our study, EGFR seemed a prognostic factor for RFS and OS. In the TCGA data, a subgroup of tissue representing poor prognosis, called "basal-like", showed abnormal expression of the EGFR pathway 18,26 .The study by Rebouissou et al suggests that this well-selected group would be a good candidate for anti-EGFR treatment, provided that patients do not have mutations in the RAS pathway that would limit the response to treatment 27 . More recently, anti-EGFR targeted therapies have been evaluated in urothelial carcinomas in a trial demonstrating the benefit of cetuximab combined with paclitaxel as second-line treatment for metastatic bladder cancer 28 .…”

MKP‑1 overexpression is associated with chemoresistance in bladder cancer via the MAPK pathway

“…It has been demonstrated that FGFR3 mutations occur in myeloma, cervix and bladder cancer ( 35 , 36 ), and is the most frequently mutated oncogene in NMIBC, primarily occurring in exons 7, 10 and 15 ( 37 ). Further studies have elucidate the FGFR3 overexpression and mutations are correlated ( 8 , 9 ). It has been demonstrated that FGFR3 is highly expressed in patients with recurrent metastatic bladder cancer ( 11 , 38 ).…”

“…It has been determined that FGFR3 mutations are correlated with FGFR3 overexpression ( 8 ). Further study has revealed that 74% of patients with bladder cancer exhibiting a high expression of FGFR3 also possessed an FGFR3 mutation, indicating that FGFR3 expression is strongly associated with FGFR3 mutation ( 9 ). Clinically, chemoresistance occurs frequently in patients with bladder cancer that exhibit an aberrant activation of FGFR3.…”

Development of RNA-FISH Assay for Detection of Oncogenic FGFR3-TACC3 Fusion Genes in FFPE Samples

“…Further studies are needed to confirm this association. In addition, the FGFR3 protein expression level and FGFR3 mutation status were found to be significantly associated[31][32], but 15–26% of FGFR3 mutant tumors showed low levels of FGFR3 expression by IHC. In the present study, 12% of FGFR3 mutant tumors showed a low level of FGFR3 protein staining (S1 Appendix).…”