151. Oncogenic activation revealed by FGFR2 genetic alterations in intrahepatic cholangiocarcinomas.
- Author
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Pu, Xiaohong, Qi, Liang, Yan, Jia Wu, Ai, Zihe, Wu, Ping, Yang, Fei, Fu, Yao, Li, Xing, Zhang, Min, Sun, Beicheng, Yue, Shen, and Chen, Jun
- Subjects
FRAMESHIFT mutation ,FLUORESCENCE in situ hybridization ,ONCOGENES ,DELETION mutation ,GENE fusion ,NUCLEOTIDE sequencing ,GENETIC mutation - Abstract
Background: Except for gene fusions, FGFR2 genetic alterations in intrahepatic cholangiocarcinomas (ICCs) have received limited attention, leaving patients harboring activating FGFR2 gene mutations with inadequate access to targeted therapies. Experimental design: We sought to survey FGFR2 genetic alterations in ICC and pan-cancers using fluorescence in situ hybridization and next-generation sequencing. We conducted an analysis of the clinical and pathological features of ICCs with different FGFR2 alterations, compared FGFR2 lesion spectrum through public databases and multicenter data, and performed cellular experiments to investigate the oncogenic potential of different FGFR2 mutants. Results: FGFR2 gene fusions were identified in 30 out of 474 ICC samples, while five FGFR2 genetic alterations aside from fusion were present in 290 ICCs. The tumors containing FGFR2 translocations exhibited unique features, which we designated as the "FGFR2 fusion subtypes of ICC". Molecular analysis revealed that FGFR2 fusions were not mutually exclusive with other oncogenic driver genes/mutations, whereas FGFR2 in-frame deletions and site mutations often co-occurred with TP53 mutations. Multicenter and pan-cancer studies demonstrated that FGFR2 in-frame deletions were more prevalent in ICCs (0.62%) than in other cancers, and were not limited to the extracellular domain. We selected representative FGFR2 genetic alterations, including in-frame deletions, point mutations, and frameshift mutations, to analyze their oncogenic activity and responsiveness to targeted drugs. Cellular experiments revealed that different FGFR2 genetic alterations promoted ICC tumor growth, invasion, and metastasis but responded differently to FGFR-selective small molecule kinase inhibitors (SMKIs). Conclusions: FGFR2 oncogenic alterations have different clinicopathological features and respond differently to SMKIs. Highlights: The findings presented in this study highlight the importance of identifying FGFR2 fusion subtypes and mutations in ICCs for both diagnosis and potential therapeutic interventions. The distinct characteristics observed in FGFR2 fusion subtypes, such as mass-forming histopathological type and CD56 positivity, can aid in accurate histopathological classification of ICC. The observation that different FGFR2 mutants in ICC nearly all promote tumor growth, invasion, and metastasis but respond differently to FGFR-selective small molecule kinase inhibitors (SMKIs) implies the need for personalized treatment strategies based on the specific FGFR2 mutation profile of each patient. These findings emphasize the potential clinical utility of targeted therapies that inhibit FGFR signaling pathways in ICC, but also underscore the importance of selecting the appropriate SMKI based on the specific FGFR2 mutation present. These findings may contribute to improved diagnosis, risk stratification, and development of targeted therapies tailored to the individual patient. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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