A Comprehensive Analysis of FGF/FGFR Signaling Alteration in NSCLC: Implications in Prognosis and Microenvironment.

Abstract

Fibroblast Growth Factor (FGF) ligands and their receptor have been identified as the potent target in non-small cell lung cancer (NSCLC). However, the clinicopathological and microenvironmental characteristics of FGF/FGFR in NSCLC remain poorly elucidated. Here, we summarize 4656 NSCLCs and analyze clinicopathological features in 478 FGF/FGFR altered cases. AI analysis and multiplex immunofluorescence staining are used to reveal microenvironment features. First, around 10.27% NSCLC carry FGF/FGFR variant. Squamous cell carcinoma (41.95%) is much more than adenocarcinoma (8.32%). In 118 pathogenic variant (PV) cases, the most frequent variant is FGF/FGFR copy number increase (83.05%), the second is FGFR gene fusion (11.86%). Surprisingly, CCND1 always co-amplifies with FGF19 (100.00%). Furthermore, FGF PV is an independent risk factor for poor outcomes (overall survival: HR = 3.781, disease-free survival: HR = 3.340). And one-third of FGFR3-TACC3 fusion cases show clear cytoplasm in histology. Either CCND1/FGF19 co-amplification or KRAS co-mutation is closely related to cigarette exposure, and KRAS co-mutation acts as an independent factor of poor prognosis. Finally, the FGF/FGFR1/NOTCH1 within RB1 variant group has a remarkably high ratio of inner-tumor CD8+ T cell infiltration, non-exhausted T cells, exhausted T^{CD8+PD-1+LAG3-} cells, and T_RM ^{CD8+CD69+CD103+}cells. Overall, this study provides a comprehensive analysis of FGF/FGFR alteration in NSCLC. The FGF/FGFR alteration mainly arises in squamous cell carcinoma. Both FGF PV and KRAS are the independent factors for poor prognosis. To our knowledge, this is the first report to describe an inflamed microenvironment recruited by NOTCH1/RB1 co-mutation, indicating potential benefit from immunotherapy.