Identification of novel and known FGFR gene fusions in Chinese non-small cell lung cancer

Abstract

Abstract Background Oncogenic fibroblast growth factor receptor (FGFR) gene fusions have been described in diverse tumor histology. FGFR inhibitors including erdafitinib have demonstrated promising results in patients whose tumors harbor FGFR gene fusions or mutations. We hereby assessed the frequency of FGFR rearrangements in the Chinese non-small cell lung cancer (NSCLC) population. Methods A total of 10,966 NSCLC patients whose tumor specimen and/or circulating cell-free DNA (cfDNA) submitted for genomic profiling by hybridization capture-based targeted next-generation sequencing (NGS) of exons and introns of cancer related genes were retrospectively reviewed. Patients’ clinical characteristics and treatment history were retrieved from the database for further evaluation. Results FGFR fusions retaining the intact kinase domain were identified in 0.11% (12/10966) of NSCLC cases examined, including 9 fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil containing protein 3 gene (TACC3) fusion-positive cases that was mostly reported in solid tumors, one fibroblast growth factor receptor 2 (FGFR2)-internexin neuronal intermediate filament protein α gene (INA) fusion that was previously reported in gliomas, one novel fibroblast growth factor receptor 4 (FGFR4)-Rap guanine nucleotide exchange factor like 1 gene (RAPGEFL1) fusion case, and one novel fibroblast growth factor receptor 1 (FGFR1) gene fusion involving the 5’UTR of Solute Carrier Family 20 Member 2 gene (SLC20A2) which may possibly drive the overexpression of FGFR1. Concomitant EGFR mutations or EGFR amplification were observed in 6 patients, four of which were previously treated with EGFR tyrosine kinase inhibitors (TKIs), but disease progressed prior to NGS tests. FGFR fusions may arise as resistance mechanism to EGFR TKI therapies in patients who carried founder EGFR alterations. No other known concurrent driver mutations were detected in the remaining 6 cases. Conclusions We hereby report a frequency of FGFR fusions of 0.11% in a large Chinses NSCLC population involving known and novel FGFR gene fusion partners including TACC3, INA, RAPGEFL1, and SLC20A2. Oncogenic FGFR fusions may arise as mechanisms of acquired resistance. Legal entity responsible for the study Geneseeq Technology Inc. Funding Has not received any funding. Disclosure Q. Ou: Full / Part-time employment, NA: Geneseeq Technology Inc. X. Wu: Leadership role, NA: Geneseeq Technology Inc. X. Wang: Full / Part-time employment, NA: Nanjing Geneseeq Technology Inc. Y.W. Shao: Leadership role, NA: Geneseeq Technology Inc. All other authors have declared no conflicts of interest.