FGFR1 protein expression and gene amplification in tongue squamous cell carcinoma and oral leukoplakia

Author(s)

Bruno Augusto Linhares Almeida Mariz

• Document type: Doctoral Thesis
• Press: Piracicaba, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Odontologia de Piracicaba
• Defense date: 2021-07-26

Examining board members

Jacks Jorge Junior; Pablo Agustin Vargas; Fernanda Viviane Mariano; Elismauro Francisco de Mendonça; Cláudia Roberta Leite Vieira de Figueiredo

• Advisor: Jacks Jorge Junior

Abstract

Fibroblast growth factor receptor 1 (FGFR1) has been associated with poor prognosis in tongue squamous cell carcinoma (TSCC). It is part of a four members family (FGFR1-4) of tyrosine kinase receptors. In oncogenesis, after its dimerization and conformational changes, downstream signaling pathways, including PI3K/Akt/mTOR, are activated, mediating proliferation, migration and survival of cancer cells. Hence, this study aimed to evaluate FGFR1 and p-AKT protein expression in TSCC and oral leukoplakia (OL), and to evaluate FGFR1 gene amplification in TSCC. For this purpose, thirty cases of TSCC were retrospectively selected from AC Camargo Cancer Center, and thirty cases of OL from the Piracicaba Dental School oral diagnosis clinic (OROCENTRO), University of Campinas (FOP-UNICAMP). Clinicopathological features and follow-up data were retrieved from the archives and digital files from both centers. Clinical features of OL were analyzed using high-resolution photographs. Oral epithelial dysplasia (OED) was analyzed by two experienced pathologists. Immunohistochemical (IHC) reactions against FGFR1 and p-AKT were performed, and quantified using a digital algorithm (Aperio Positive Pixel Count v9 Software). Cases were classified as presenting "low" or "high" expression according to the group median. Fluorescent in situ hybridization (FISH) reactions were performed using a FGFR1/CEN8 dual color amplification probe (Zytovision). After analysis using a fluorescence microscope, cases presenting a FGFR1/CEN8 ratio ?2 were considered amplificated. Clinical appearance and dysplasia grade were correlated with OL malignant transformation. OL cases presenting high FGFR1 expression showed a higher risk of malignant transformation (p=0.016, HR: 7.3, 95%CI: 1.4-37.4). p-AKT showed faint to no expression in OL, which did not correlate with dysplasia grade or malignant transformation. In the IHC analysis, high expression of FGFR1 was significantly associated to poor overall survival (OS) (p=0.024; HR: 4.9, 95%CI: 1.2-19.9). Cases presenting double FGFR1/p-AKT overexpression (n=8) showed markedly impaired OS (p=0.020; HR: 6.4, 95%CI: 1.3-31.1) and disease-free survival (DFS) (p=0.001, HR: 13.0, 95%CI: 3.0-55.7). FGFR1 amplification was observed in 16.6% of TSCC cases, being correlated with vascular and neural invasion (p=0.001 and 0.017, respectively), but not with FGFR1 protein expression, OS, or DFS. Taken together, our findings suggest FGFR1 protein expression is a potential prognostic factor in OL and TSCC (AU)

• FAPESP's process: 18/24715-2 - FGF-2, FGFR-1, PI3K, Akt and COX-2 expression in Oral Leucoplakia, primary and metastatic Oral Squamous Cell Carcinoma
• Grantee: Bruno Augusto Linhares Almeida Mariz
• Support Opportunities: Scholarships in Brazil - Doctorate