Frequency of Fibroblast Growth Factor Receptor 1 gene amplification in oral tongue squamous cell carcinomas and associations with clinical features and patient outcome
Introduction
Carcinomas of the oral cavity have a poorer prognosis compared with other head and neck subsites.1 Furthermore, within the oral cavity, oral tongue squamous cell carcinomas (OTSCC) have the worst prognosis.2 Early stage OTSCC are typically managed with surgery with curative intent, however there remains a significant rate of local locoregional failure such that the overall outcome for early stage OTSCC is inferior to outcomes for later stage cancers of other oral cavity sites.2 While HPV status is now known to play a causative role in a significant proportion of head and neck squamous cell carcinoma (HNSCC) patients in the oropharynx,3 the involvement of HPV in OTSCC remains unclear, though most studies suggest that HPV infection is not significant in the pathogenesis of OTSCC.[4], [5] The lack of a pathological explanation for the aggressive tumour biology of OTSCC, and limitations of traditional clinico-pathological criteria to appropriately stratify patients for particular treatments, suggest that further research is needed to identify prognostic and predictive biomarkers for existing therapies and also to identify novel molecular targets of therapeutic utility in OTSCC.
The Fibroblast Growth Factor (FGF) family consists of at least 23 secreted glycoproteins that bind to and signal through four highly conserved trans-membrane receptor tyrosine kinases, FGF receptors 1–4.[6], [7] Normally, FGF signalling regulates many developmental pathways and physiological processes such as proliferation, differentiation and survival in a variety of cell types.8 There is strong evidence that deregulated FGF signalling plays a role in the pathogenesis of many cancers, and in particular, evidence of an oncogenic role for FGFR1. Several recent studies have investigated FGFR1 gene amplification in squamous cell carcinoma (SCC) of the lung.[9], [10], [11], [12] Weiss et al.9 found frequent and focal FGFR1 amplification in 22% of cases, a finding confirmed by a subsequent study reporting FGFR1 amplification in 20% of pulmonary squamous carcinomas.10 Dutt et al.11 independently found an FGFR1 amplification rate of 21% in lung SCC using SNP arrays. Kim et al.12 found an amplification rate of 13% in surgically resected SCC of the lung. Significantly, in vitro data indicate that FGFR1 amplified lung SCC cells are dependent on FGFR1 signalling for survival and are sensitive to FGFR inhibitors.[9], [11] Less frequent amplifications in the FGFR1 gene have also been described in several other cancer types including breast,13 oesophageal,14 bladder,15 prostate16 and ovarian.17 In 2007, Freier et al.18 demonstrated that 17.4% of oral cavity squamous cell carcinomas harboured amplifications of FGFR1 suggesting that this may be a relevant therapeutic target in this malignancy.
The potential to exploit FGFR1 as a therapeutic target has led to the development of several potent and specific FGFR1 inhibitors, which are at various stages of preclinical and early clinical development.6 In the present study we have utilised a fluorescence in situ hybridisation (FISH) assay to investigate the frequency of FGFR1 gene amplification in a cohort of 123 OTSCC patients, and examined the associations of FGFR1 gene copy number variations with clinical features and patient outcome.
Section snippets
Patients
The study comprised a cohort of 123 patients treated for oral tongue squamous cell carcinoma at our institution between 2002 and 2008. OTSCC was defined by a multidisciplinary team as a tumour arising from the anterior two-thirds of the tongue. The clinical patient and tumour characteristics are summarised in Table 1. Patients with a history of tobacco use were defined by a clinician as an “ever-smoker” or a “non-smoker”. A history of alcohol use was defined as greater than 20 g of alcohol per
Patient characteristics
FFPE tumour blocks were obtained for 123 patients, all of which were included in the TMA blocks. The clinicopathological characteristics of the patients are summarised in Table 1. The median age of patients at diagnosis was 59 (range 21–93). Males comprised 65% of the patients. The majority of patients, 71%, had smoking histories while 38% had a history of alcohol use. The treatment regimens consisted of surgery alone (25%), surgery with adjuvant radiotherapy (30%), surgery with adjuvant
Discussion
In the present study we have shown that copy number variations of the FGFR1 gene are relatively common in OTSCC with approximately 10% of cases exhibiting FGFR1 gene amplification. We have also found that FGFR1 gene amplification is significantly associated with a history of smoking and tends to occur more frequently in males. There were no survival differences between FGFR1 amplified and non-amplified patients.
Using the FGFR1 amplification definition as proposed by Weiss et al.9 we found 9.3%
Conflict of interest statement
None declared.
Acknowledgement
The authors would like to thank David Byrne for expert technical assistance.
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2018, Seminars in Cancer BiologyCitation Excerpt :Other components of the PI3K pathway are frequently altered including PTEN mutations or gene copy loss [19]. Alterations in FGFR1(fibroblast growth factor receptor 1), including gene amplification, are more common in HPV-negative HNSCC than in HPV-positive HNSCC [18,25]. Similar findings have been reported in lung SCC, where FGFR1 amplification or FGFR1 RNA expression may predict response to FGFR inhibitors [26].
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2016, Bioorganic and Medicinal ChemistryCitation Excerpt :It was demonstrated that inhibition of FGFR1 by a specific kinase inhibitor or a dominant-negative FGFR1 construct led to significantly decreased proliferation, clonogenicity, migration, spheroid formation, and G1 cell cycle arrest in several mesothelioma cell lines.11 FGFR1 has been shown to be involved in the pathogenesis of oral tongue squamous cell carcinomas,12 sinonasal cancer,13 gastric cancer,14 pancreatic cancer,15,16 colorectal cancer,17,18 renal cell carcinoma,19,20 prostate cancer,21,22 bladder cancer23 and acute myeloid leukemia.24 Recently, it was reported, that oncogenic mutations of FGFR1 occurred in a subset of patients with pilocytic astrocytoma with worse outcome.25
Fibroblast Growth Factor (FGF) Receptor/FGF Inhibitors: Novel Targets and Strategies for Optimization of Response of Solid Tumors
2015, Seminars in OncologyCitation Excerpt :FGFR1 amplification seems to be mutually exclusive with human papilloma virus infection, implying completely different carcinogenic footprints. May be for this reason, FGFR1 amplification is more frequently detected in hypopharynx and larynx tumors, and it has also been described in a subset (9%) of oral tongue squamous cell carcinomas.28 Preclinical results have revealed an autocrine loop with frequent coexpression of FGF2 and FGFRs in HNSCC cell lines, that alone or in combination with EGFR, drive cell proliferation and transformation.29
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