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. 2016 Feb;5(2):275-84.
doi: 10.1002/cam4.595. Epub 2015 Dec 28.

Fibroblast growth factor receptor 3 protein is overexpressed in oral and oropharyngeal squamous cell carcinoma

Koos Koole  1   2 , Pauline M W van Kempen  3 , Justin E Swartz  3 , Ton Peeters  1 , Paul J van Diest  1 , Ron Koole  2 , Robert J J van Es  2 , Stefan M Willems  1   4
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Fibroblast growth factor receptor 3 protein is overexpressed in oral and oropharyngeal squamous cell carcinoma

Koos Koole et al. Cancer Med. 2016 Feb.

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is a member of the fibroblast growth factor receptor tyrosine kinase family. It has been identified as a promising therapeutic target in multiple types of cancer. We have investigated FGFR3 protein expression and FGFR3 gene copy-numbers in a single well-documented cohort of oral and oropharyngeal squamous cell carcinoma. Tissue microarray sets containing 452 formalin-fixed paraffin-embedded tissues were immunohistochemically stained with an anti-FGFR3 antibody and hybridized with a FGFR3 fluorescence in situ hybridization probe. FGFR3 protein expression was correlated with clinicopathological and survival data, which were retrieved from electronic medical records. FGFR3 mRNA data of 522 head and neck squamous cell carcinoma (HNSCC) were retrieved from The Cancer Genome Atlas (TCGA). Fibroblast growth factor receptor 3 (FGFR3) protein was overexpressed in 48% (89/185) of oral and 59% (124/211) of oropharyngeal squamous cell carcinoma. Overexpression of FGFR3 protein was not related to overall survival or disease-free survival in oral (HR[hazard ratio]: 0.94; 95% CI: 0.64-1.39; P = 0.77, HR: 0.94; 95% CI: 0.65-1.36; P = 0.75) and oropharyngeal squamous cell carcinoma (HR: 1.21; 95% CI: 0.81-1.80; P = 0.36, HR: 0.42; 95% CI: 0.79-1.77; P = 0.42). FGFR3 mRNA was upregulated in 3% (18/522) of HNSCC from the TCGA. The FGFR3 gene was gained in 0.6% (1/179) of oral squamous cell carcinoma but no amplification was found in oral and oropharyngeal squamous cell carcinoma. In conclusion, FGFR3 protein is frequently overexpressed in oral and oropharyngeal squamous cell carcinoma. Therefore, it may serve as a potential therapeutic target for FGFR3-directed therapies in oral and oropharyngeal squamous cell carcinoma.

Keywords: fibroblast growth factor receptor 3; oral cancer; oropharyngeal cancer; therapeutic target.

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Figures

Figure 1
Figure 1
Microscopic images of immunohistochemical staining for FGFR3 protein at 10× and 40× magnification and fluorescence in situ hybridization of the FGFR3 gene at 100× magnification. Tissue microarray slides containing oral and oropharyngeal squamous cell carcinoma cores (0.6 mm) were immunohistochemically stained for FGFR3 protein using an anti‐FGFR3 antibody. Fluorescence in situ hybridization of the FGFR3 gene was performed on another set of tissue microarray slides. Strong immunohistochemical staining was observed in (A) oral squamous cell carcinoma and (B) oropharyngeal squamous cell carcinoma overexpressing FGFR3 protein. No staining was observed in (C) oral squamous cell carcinoma and (D) oropharyngeal squamous cell carcinoma not expressing FGFR3 protein. Normal tonsillar tissue (E) showed no staining for FGFR3 protein. (F) FGFR3 copy‐number gain and (G) normal FGFR3 gene copy‐numbers in oral squamous cell carcinoma. The red probe signal is hybridized to the FGFR3 gene and the green probe signal is hybridized to the IGH gene. FGFR3, fibroblast growth factor receptor 3; OPSCC, oropharyngeal squamous cell carcinoma; OSCC, oral squamous cell carcinoma; IGH, immunoglobulin heavy locus.
Figure 2
Figure 2
Prevalence of FGFR3 protein overexpression and FGFR3 mRNA levels in head and neck squamous cell carcinoma. (A) Tissue microarray slides containing oral and oropharyngeal squamous cell carcinoma cores (0.6 mm) were immunohistochemically stained for FGFR3 protein using an anti‐FGFR3 antibody. FGFR3 protein was overexpressed in 48% (89/185) of oral squamous cell carcinoma and 59% (124/211) of oropharyngeal squamous cell carcinoma. Within the oropharyngeal population, FGFR3 protein was overexpressed in 53% (20/38) of HPV‐positive and 59% (97/165) of HPV‐negative oropharyngeal squamous cell carcinoma. (B) Data on FGFR3 mRNA levels of 522 HNSCC were retrieved from The Cancer Genome Atlas (TCGA) Research Network on the 29th of September, 2015. FGFR3 mRNA levels were upregulated in 3% (18/522) of all HNSCC and normal in all other HNSCC head and neck squamous cell carcinoma. FGFR3, fibroblast growth factor receptor 3; HPV, human papillomavirus; OPSCC, oropharyngeal squamous cell carcinoma; OSCC, oral squamous cell carcinoma.
Figure 3
Figure 3
Kaplan–Meier overall survival curves for FGFR3 protein expression in oral and oropharyngeal squamous cell carcinoma. Tissue microarray slides containing cores (0.6 mm) of 212 oral and 240 oropharyngeal squamous cell carcinoma were immunohistochemically stained for FGFR3 protein using an anti‐FGFR3 antibody. FGFR3 protein expression was not related to overall survival in (A) oral squamous cell carcinoma (HR: 0.94; 95% CI: 0.64–1.39; P = 0.769) and (B) oropharyngeal squamous cell carcinoma (HR: 1.21; 95% CI: 0.81–1.80; P = 0.361). Similarly, FGFR3 protein expression was not related to overall survival in (C) HPV‐positive (HR: 0.74; 95% CI: 0.20–2.77; P = 0.657) and (D) HPV‐negative oropharyngeal squamous cell carcinoma (HR: 1.28; 95% CI: 0.84–1.97; P = 0.249). FGFR3, fibroblast growth factor receptor 3; HPV, human papillomavirus; HR, hazard ratio.
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