Huang Ziling, Li Leyao, Cai Xu, Wang Shen, Jia Yun, Li Yuan
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China.
Thorac Cancer. 2025 Feb;16(4):e70016. doi: 10.1111/1759-7714.70016.
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 cells, and T 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.
成纤维细胞生长因子（FGF）配体及其受体已被确定为非小细胞肺癌（NSCLC）的有效靶点。然而，NSCLC中FGF/FGFR的临床病理和微环境特征仍未得到充分阐明。在此，我们总结了4656例NSCLC，并分析了478例FGF/FGFR改变病例的临床病理特征。采用人工智能分析和多重免疫荧光染色来揭示微环境特征。首先，约10.27%的NSCLC存在FGF/FGFR变异。鳞状细胞癌（41.95%）的变异率远高于腺癌（8.32%）。在118例致病性变异（PV）病例中，最常见的变异是FGF/FGFR拷贝数增加（83.05%），其次是FGFR基因融合（11.86%）。令人惊讶的是，CCND1总是与FGF19共同扩增（100.00%）。此外，FGF PV是预后不良的独立危险因素（总生存期：HR = 3.781，无病生存期：HR = 3.340）。并且三分之一的FGFR3-TACC3融合病例在组织学上显示细胞质清晰。CCND1/FGF19共同扩增或KRAS共突变均与吸烟暴露密切相关，且KRAS共突变是预后不良的独立因素。最后，RB1变异组内的FGF/FGFR1/NOTCH1具有显著高比例的肿瘤内CD8+ T细胞浸润、非耗竭性T细胞、耗竭性T细胞和T细胞。总体而言，本研究对NSCLC中FGF/FGFR改变进行了全面分析。FGF/FGFR改变主要发生在鳞状细胞癌中。FGF PV和KRAS均为预后不良的独立因素。据我们所知，这是第一份描述由NOTCH1/RB1共突变招募的炎症微环境的报告，表明免疫治疗可能有益。
