Evaluation of fibroblast growth factor receptor 2 expression, heterogeneity and clinical significance in gastric cancer

Abstract

Introduction: Fibroblast growth factor receptor 2 (FGFR2) gene amplification promotes overexpression of FGFR2 protein, a target for therapeutics now in clinical development for gastric cancer (GC) patients. This study aimed to evaluate the protein and mRNA expressions of fibroblast growth factor receptor 2 (FGFR2) by immunohistochemistry (IHC) and mRNA in situ hybridization (ISH), respectively, and to assess the heterogeneity of FGFR2 expression in gastric cancer. Methods: The study cohorts included patients who had gastric cancer and have undergone surgical resection from January 1, 2004, to December 31, 2005. Cases from 2 cohorts of patients with gastric cancer from the year 2005 (n = 362, training set) and 2004 (n = 413, validation set) were selected for the construction of tissue microarrays. One hundred thirty-five matched metastatic lymph nodes (LNs) were also selected from training set. They were used to assess the IHC and mRNA ISH status. DNA fluorescence in situ hybridization (FISH) for FGFR2 was performed in training set. For 188 patients, FGFR2 status by DNA FISH was available. Results: All FGFR2-amplified cases (n = 5) showed FGFR2 protein and mRNA overexpressions (P < 0.001) from training set. Kaplan-Meier survival analysis revealed that FGFR2 protein and mRNA overexpressions were significantly associated with poor overall survival from training set (P < 0.001 and P = 0.012, respectively), whereas no significant association with survival was observed in validation set. FGFR2 protein overexpression was found to be a negative prognostic indicator on multivariate analysis when the 2 cohorts were combined (P = 0.043). Intratumoral heterogeneity was defined as different results between tissue microarray cores. In FGFR2-positive primary gastric cancers, heterogeneous FGFR2 protein and mRNA overexpressions were observed in 5 of 9 (55.5%) and 18 of 21 (85.7%) cases, respectively. Discordant FGFR2 protein and mRNA expressions were observed in 5 of 9 (55.5%) and 4 of 14 (28.6%) pairings of primary tumor and regional lymph node metastases, respectively. Conclusions: IHC using FGFR2 antibody would be suitable for evaluating FGFR2 overexpression. Intratumoral heterogeneity and discrepant FGFR2 results in primary and regional metastatic lymph node are common in gastric cancer.