FGFR2 overexpression and compromised survival in diffuse-type gastric cancer in a large central European cohort.

Thorben Schrumpf,Jochen Haag,Christoph Röcken,Sandra Krüger,Hans-Michael Behrens,Pirkko L Härkönen

doi:10.1371/journal.pone.0264011

Abstract

The significance of fibroblast growth factor receptor 2 (FGFR2) in gastric cancer (GC) has been studied predominantly in Asian patient cohorts. Data on White patients are scarce. Here, we aimed to independently validate the expression and putative tumor biological significance of FGFR2 in a large non-Asian GC cohort. Immunohistochemistry (IHC) was performed on large-area tissue sections from 493 patients with GC and evaluated using the HScore. GCs with moderate and strong FGFR2 expression were studied for Fgfr2 amplification using chromogenic in situ hybridization (CISH). Median overall survival was determined using the Kaplan-Meier method. The majority [240 (99.1%)] of FGFR2-positive GCs showed a variable combination of staining intensities with marked intratumoral heterogeneity, including weak [198 (40.2%) cases], moderate [145 (29.4%)], and strong [108 (21.9%)] staining in diverse combinations. 250 (50.9%) GCs expressed no FGFR2. Fgfr2 gene amplification was found in 40% of selected cases with high protein expression and was also heterogeneous at the cell level. FGFR2 protein expression did not correlate with patient survival in the entire cohort However, using different cutoff values, a negative correlation between FGFR2-expression and patient outcome was found for diffuse-type GC. FGFR2 expression was associated with a lower tumor grade and intestinal phenotype (p≤0.0001). FGFR2-positive diffuse-type GCs classify a small subset of patients with a poor tumor specific survival (5.29±1.3 vs. 14.67±1.9 months; p = 0.004).

Highlights

Despite the declining incidence of gastric cancer (GC) in recent decades, it remains the fifth most common malignancy and third leading cause of cancer-related deaths worldwide [1]
We found no significant correlation between the intracellular localization of fibroblast growth factor receptor 2 (FGFR2) and any clinicopathological patient characteristic (S2 Table)
Our study on a large and well-characterized White patient population showed that FGFR2 is expressed heterogeneously in GC, partly related to heterogeneous Fgfr2 amplification, sharing features with other tyrosine kinase receptors (TKRs), such as HER2 or MET

Summary

Introduction

Despite the declining incidence of gastric cancer (GC) in recent decades, it remains the fifth most common malignancy and third leading cause of cancer-related deaths worldwide [1]. At the time of diagnosis, approximately twothirds of the patients present with an advanced disease stage [3]. Curative surgery is no longer an option in most patients. Palliative chemotherapy and supportive therapy remain the only available treatment [4]. Amplification of different tyrosine kinase receptors (TKRs) has been described in GC [5].

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