FGFR1 Amplification Is Often Homogeneous and Strongly Linked to the Squamous Cell Carcinoma Subtype in Esophageal Carcinoma.

Katharina Von Loga,Jule Kohlhaussen,Ronald Simon,Till Krech,Stefan Steurer,Frank Jacobsen,Lia Burkhardt,Susanne Burdak-Rothkamm,Guido Sauter,Amit Dutt

doi:10.1371/journal.pone.0141867

Abstract

Background and AimsAmplification of the fibroblast growth factor receptor 1 (FGFR1) is believed to predict response to multi-kinase inhibitors targeting FGFR1. Esophageal cancer is an aggressive disease, for which novel targeted therapies are highly warranted.MethodsThis study was designed to investigate the prevalence and clinical significance of FGFR1 amplification in a tissue microarray containing 346 adenocarcinomas and 254 squamous cell carcinomas of the esophagus, using dual-labeling fluorescence in situ hybridization (FISH) analysis.Results FGFR1 amplification, defined as a ratio of FGFR1:centromere 8 copy numbers ≥ 2.0, was more frequently seen in squamous cell carcinoma (8.9% of 202 interpretable cases) than in adenocarcinoma (1.6% of 308; p<0.0001). There was no association between FGFR1 amplification and tumor phenotype or clinical outcome. To study potential heterogeneity of FGFR1 amplification, all available tumor blocks from 23 FGFR1 amplified tumors were analyzed on conventional large sections. This analysis revealed complete homogeneity of FGFR1 amplification in 20 (86.9%) primary tumors and in all available lymph node metastases. Remarkably, FGFR1 amplification was also seen in dysplasia adjacent to tumor in 6 of 9 patients with FGFR1 amplified primary cancers.ConclusionsIn conclusion, FGFR1 amplification occurs in a relevant subgroup of carcinomas of the esophagus and may play a particular role for development of squamous cell cancers. The high homogeneity of FGFR1 amplification suggests that patients with FGFR1 amplified esophageal cancers may particularly benefit from anti-FGFR1 therapies and prompt for clinical studies in this tumor type.

Highlights

Esophageal cancer is an aggressive disease presenting with two histologically and genetically distinct subtypes, i.e. adeno- and squamous cell carcinoma (EADC and ESCC)
fibroblast growth factor receptor 1 (FGFR1) amplification, defined as a ratio of FGFR1:centromere 8 copy numbers 2.0, was more frequently seen in squamous cell carcinoma (8.9% of 202 interpretable cases) than in adenocarcinoma (1.6% of 308; p
FGFR1 amplification occurs in a relevant subgroup of carcinomas of the esophagus and may play a particular role for development of squamous cell cancers

Summary

Introduction

Esophageal cancer is an aggressive disease presenting with two histologically and genetically distinct subtypes, i.e. adeno- and squamous cell carcinoma (EADC and ESCC). There is growing evidence that targeting of the fibroblast growth factor receptor 1 (FGFR1) holds promising clinical potential [11,12]. Little is known about the clinical significance of FGFR1 amplification in esophageal cancer or about possible differences between histological subtypes. Reported FGFR1 amplification frequencies in studies on 32–189 esophageal cancers range between 6–21% in squamous cell cancers [24,25] and 9% in adenocarcinomas [25], but the impact on patient prognosis is largely unknown. Amplification of the fibroblast growth factor receptor 1 (FGFR1) is believed to predict response to multi-kinase inhibitors targeting FGFR1. Esophageal cancer is an aggressive disease, for which novel targeted therapies are highly warranted

Methods

Results

Conclusion