Fibroblast growth factor receptor 1 gene amplification in pancreatic ductal adenocarcinoma

• Published in: Histopathology 2013-08, Vol.63 (2), p.157-166
• Main Authors: Lehnen, Nils C, von Mässenhausen, Anne, Kalthoff, Holger, Zhou, Hui, Glowka, Tim, Schütte, Ute, Höller, Tobias, Riesner, Katarina, Boehm, Diana, Merkelbach-Bruse, Sabine, Kirfel, Jutta, Perner, Sven, Gütgemann, Ines
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adult; Aged; Aged, 80 and over; amplification; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cells; DNA, Neoplasm - genetics; Female; fibroblast growth factor receptor 1; fluorescence in-situ hybridization; Gene Amplification; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Middle Aged; Mutation; Pancreas; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Prognosis; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Tissue Array Analysis
• ISSN: 0309-0167; 1365-2559
• DOI: 10.1111/his.12115

Aims Pancreatic ductal adenocarcinomas (PDACs) are chemoresistant, resulting in extremely poor survival of patients; therefore, novel molecular targets, even in small subsets of genetically characterized tumours, are urgently needed. Tyrosine kinase receptor inhibitors (TKIs) are already in clinical use. The aims of this study were to examine the gene copy number and expression of fibroblast growth factor receptor 1 (FGFR1) in 155 patients with PDAC, and investigate the effects of the FGFR‐specific inhibitor BGJ398 on FGFR1‐amplified pancreatic tumour cells in vitro. Methods and results Fluorescence in‐situ hybridization (FISH) and immunohistochemical analysis of 155 PDACs were performed using tissue microarrays. Amplification of FGFR1 was found in 2.6% (4/155) of cases. Four per cent of tumours (5/125) were shown to express FGFR1 by immunohistochemistry. Sequence analysis demonstrated an activating KRAS mutation (exon 2) in all FGFR1‐amplified cases. The FGFR1‐amplified pancreatic carcinoma cell line PT45P1 showed high levels of FGFR1 mRNA and protein expression. Proliferation of this cell line can be inhibited using the FGFR1 inhibitor BGJ398. Conclusions FGFR1 represents a potential new therapeutic target in a subset of patients harbouring FGFR1‐amplified tumours. Identification of pancreatic cancers harbouring FGFR1 amplification may be important in preselecting patients and/or interpreting clinical studies using TKIs.