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
Processing time: 106 Days and 14.1 Hours
ARTICLE HIGHLIGHTS
Research 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) especially members of the Fibroblast Growth Receptor (FGFR)-family. Single-nucleotide polymorphism (SNP) Arg388 allele of the Fibroblast Growth Factor Receptor 4 (FGFR4) is associated with a reduced overall survival in patients with cancers of various types. We speculate that FGFR4 expression and Gly388Arg polymorphism are associated with worse survival in patients with HSNCC. To investigate the potential clinical significance of the FGFR4 Arg388 allele 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.

Research motivation

We undertook the study to investigate the impact of FGFR4 expression in tumor tissue of HNSCC and the FGFR4 SNP Glycine to Arginine at position388 with regards to clinical pathological characteristics in a large patient cohort. Our previous study revealed significant results in a smaller group of patients with HNSCC, where this SNP was associated with reduced survival and tumor progression whilst strong evidence for implication of this SNP was demonstrated in other tumor entities. In the context of exploring future tumor therapeutic interventions we aimed at providing strong evidence a possibly relevant useful target.

Research objectives

The aim of this study was to evaluate the relevant impact of FGFR4 expression and FGFR4 SNP Gly/Arg388 in tumor progression of patients with HNSCC utilizing a large cohort analysis for the respective aspects and correlate it with the patients’ clinical data with special emphasis on patients’ overall survival and disease progression.

Research methods

We analyzed tumor specimens of 284 patients with HNSCC and used Immunhistochemistry to assess FGFR4 expression in tumor tissues and PCR-RLFP to identify FGFR4 genotype in the same tumor samples. Obtained data was correlated in a comprehensive statistical analysis, including multivariant analysis and logistic regression models.

Research results

We have shown that FGFR4 expression was almost evenly distributed among 3 groups with strong, mediate and low expression levels. FGFR4 polymorphism Arg388 was prevalent in 33.8% of patient. Strong FGFR4 expression in tumor cells was significantly associated with worse overall survival. Furthermore, FGFR4 Arg388 genotype was strongly associated with tumor progression, lymph node metastasis and reduced disease-free survival.

Research conclusions

Our results show the relevant impact of FGFR4 signaling for tumor progression and worse survival in patients with HNSCC. These results confirm previous small-scale studies with similar outcomes, now providing statistically robust results in order to underline the potential to develop new target therapies in HNSCC.

Research perspectives

Facing the complexity of tumor biology with implications of multiple alterated pathways in tumor development while therapy success in cancer therapy is still limited and therapies are mostly limited to surgery and radiochemotherapy, there is still a strong need for new targets in order to improve therapies in a multimodal setting. Obviously, further investigations are mandatory to better understand the mechanisms how altered signaling pathways in cancer affect tumor biology for future development of new target therapies.