Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Mar 24, 2019; 10(3): 136-148
Published online Mar 24, 2019. doi: 10.5306/wjco.v10.i3.136
Fibroblast growth factor receptor 4 single nucleotide polymorphism Gly388Arg in head and neck carcinomas
Eva Wimmer, Stephan Ihrler, Olivier Gires, Sylvia Streit, Wolfgang Issing, Christoph Bergmann
Eva Wimmer, Olivier Gires, Wolfgang Issing, Christoph Bergmann, Department of Otorhinolaryngology, Ludwig-Maximilians-University, Munich 81377, Germany
Stephan Ihrler, Institute of Pathology, Ludwig-Maximilians-University, Munich 80337, Germany
Olivier Gires, Clinical Cooperation Group Personalized Radiotherapy of Head and Neck Tumors, Neuherberg 71083, Germany
Sylvia Streit, Department of Molecular Biology, Max-Planck-Institute for Biochemistry, Planegg 82152, Germany
Wolfgang Issing, ENT Department, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, United Kingdom
Christoph Bergmann, Department of Otorhinolaryngology, University of Duisburg-Essen, Essen 45147, Germany
Author contributions: Wimmer E performed the majority of experiments, analyzed the data and wrote the paper, Ihrler S conducted analysis of histology, Gires O helped writing the paper, Streit S conducted experiments, Issing W designed and coordinated the research; Bergmann C performed experiments, analyzed the data, conducted statistical analysis and helped the write the paper.
Institutional review board statement: The study was reviewed and approved by the Ludwig-Maximilian University Institutional Review Board.
Institutional animal care and use committee statement: Not applicable to this study.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Data sharing statement: Dataset available from the corresponding author at Christoph.bergmann@uk-essen.de.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Christoph Bergmann, MD, PhD, Assistant Professor, Senior Lecturer, Surgeon, Department of Otorhinolaryngology, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany. christoph.bergmann@uk-essen.de
Telephone: +49-151-40512955
Received: December 6, 2018
Peer-review started: December 6, 2018
First decision: December 30, 2018
Revised: January 16, 2019
Accepted: January 30, 2019
Article in press: January 30, 2019
Published online: March 24, 2019
Abstract
BACKGROUND

Head and neck squamous cell carcinoma (HNSCC) is considered to be a progressive disease resulting from alterations in multiple genes regulating cell proliferation and differentiation like receptor tyrosine kinases (RTKs) and members of the fibroblast growth factor receptors (FGFR)-family. Single-nucleotide polymorphism (SNP) Arg388 of the FGFR4 is associated with a reduced overall survival in patients with cancers of various types. We speculate that FGFR4 expression and SNP is associated with worse survival in patients with HSNCC.

AIM

To investigate the potential clinical significance of FGFR4 Arg388 in the context of tumors arising in HNSCC, a comprehensive analysis of FGFR4 receptor expression and genotype in tumor tissues and correlated results with patients’ clinical data in a large cohort of patients with HNSCC was conducted.

METHODS

Surgical specimens from 284 patients with HNSCC were retrieved from the Institute of Pathology at the Ludwig-Maximilian-University in Germany. Specimens were analyzed using immunohistochemistry and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The expression of FGFR4 was analyzed in 284 surgical specimens of HNSCC using immunohistochemstry. FGFR4 polymorphism was detected by PCR-RFLP. Patients’ clinical data with a minimum follow-up of 5 years were statistically evaluated with a special emphasis on survival analysis employing Kaplan-Meier estimator and Cox regression analysis.

RESULTS

Concerning the invasive tumor areas the intensity of the FGFR4 expression was evaluated in a four-grade system: no expression, low expression, intermediate and high expression. FGFR4 expression was scored as “high” (+++) in 74 (26%), “intermediate” (++) in 103 (36.3%), and “low” (+) in 107 (36.7%) cases. Analyzing the FGFR4 mutation it was found in 96 tumors (33.8%), 84 of them (29.6%) having a heterozygous and 12 (4.2%) homozygous mutated Arg388 allele. The overall frequency concerning the mutant alleles demonstrated 65% vs 34% mutated alleles in general. FGFR4 Arg388 was significantly associated with advanced tumor stage (P < 0.004), local metastasis (P < 0.0001) and reduced disease-free survival (P < 0.01). Furthermore, increased expression of FGFR4 correlated significantly with worse overall survival (P < 0.003).

CONCLUSION

In conclusion, the FGFR4 Arg388 genotype and protein expression of FGFR4 impacts tumor progression in patients with HNSCC and may present a useful target within a multimodal therapeutic intervention.

Keywords: : Fibroblast growth factor receptor 4, Single-nucleotide polymorphism, Head and neck squamous cell carcinoma, Reduced survival, Cancer progression, Polymerase chain reaction, Immunohistochemistry, Outcome

Core tip: Single-nucleotide polymorphism Arg388 of the fibroblast growth factor receptor-4 (FGFR4) is associated with a reduced overall survival in patients with various cancers. Here, the potential clinical significance of FGFR4 Arg388 was investigated in the context of head and neck carcinoma in 284 patients using immunohistochemistry and polymerase chain reaction. Advanced tumor stage and local metastasis was significantly associated with reduced disease-free survival in mutant FGFR4 Arg388 carriers. Increased expression of FGFR4 correlated significantly with worse overall survival impacting tumor progression in patients with head and neck squamous cell carcinoma and may present a useful target within a multimodal therapeutic intervention.