Fibroblast growth factor receptor 4 single nucleotide polymorphism Gly388Arg in head and neck carcinomas

作     者：Eva Wimmer Stephan Ihrler Olivier Gires Sylvia Streit Wolfgang Issing Christoph Bergmann 

作者机构：Department of OtorhinolaryngologyLudwig-Maximilians-University Institute of PathologyLudwig-Maximilians-University Clinical Cooperation Group Personalized Radiotherapy of Head and Neck Tumors Department of Molecular BiologyMax-Planck-Institute for Biochemistry ENT DepartmentFreeman Hospital Department of OtorhinolaryngologyUniversity of Duisburg-Essen 

出 版 物：《World Journal of Clinical Oncology》 (世界临床肿瘤学杂志（英文版）)

年 卷 期：2019年第10卷第3期

页      面：136-148页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

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

摘      要：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. Singlenucleotide 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.