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Ref Type Journal Article
PMID (37964396)
Authors Pu X, Qi L, Yan JW, Ai Z, Wu P, Yang F, Fu Y, Li X, Zhang M, Sun B, Yue S, Chen J
Title Oncogenic activation revealed by FGFR2 genetic alterations in intrahepatic cholangiocarcinomas.
Journal Vol Issue Date Pages Journal Short Title
Cell & bioscience 13 1 2023 Nov 14 208 Cell Biosci
URL
Abstract Text 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.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.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).FGFR2 oncogenic alterations have different clinicopathological features and respond differently to SMKIs.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 H167_N173del deletion gain of function FGFR2 H167_N173del results in the deletion of seven amino acids in Ig-like C2-type domain 2 of the Fgfr2 protein from amino acids 167 to 173 (UniProt.org). H167_N173del results in cell transformation (J Clin Oncol 38, 2020 (suppl 4; abstr 567), PMID: 33926920), increased proliferation, invasion, and migration (PMID: 37964396), anchorage-independent growth, constitutive activation of Fgfr2 kinase activity in culture, and tumor formation in an in vivo model (PMID: 33926920).
FGFR2 I288_D304del deletion gain of function - predicted FGFR2 I288_D304del results in the deletion of 17 amino acids in Ig-like C2-type domain 3 of the Fgfr2 protein from amino acids 288 to 304 (UniProt.org). I288_D304del results in increased proliferation, migration, and invasion in cultured cells (PMID: 37964396), and therefore, is predicted to lead to a gain of Fgfr2 protein function.
FGFR2 I548Wfs*8 frameshift gain of function - predicted FGFR2 I548Wfs*8 indicates a shift in the reading frame starting at amino acid 548 and terminating 8 residues downstream causing a premature truncation of the 821 amino acid Fgfr2 protein (UniProt.org). I548Wfs*8 results in increased proliferation and invasion in cultured cells (PMID: 37964396), and therefore, is predicted to lead to a gain of Fgfr2 protein function.
FGFR2 K545del deletion gain of function - predicted FGFR2 K545del results in the deletion of an amino acid in the protein kinase domain of the Fgfr2 protein at amino acid 545 (UniProt.org). K545del results in increased proliferation, migration, and invasion in 2 of 3 cell lines in culture (PMID: 37964396), and therefore, is predicted to lead to a gain of Fgfr2 protein function.
FGFR2 N631_M640del deletion gain of function - predicted FGFR2 N631_M640del results in the deletion of 10 amino acids in the protein kinase domain of the Fgfr2 protein from amino acids 631 to 640 (UniProt.org). N631_M640del results in increased proliferation, migration, and invasion in cultured cells (PMID: 37964396), and therefore, is predicted to lead to a gain of Fgfr2 protein function.
FGFR2 R255W missense unknown FGFR2 R255W lies within the extracellular domain of the Fgfr2 protein (UniProt.org). R255W has been identified in sequencing studies (PMID: 37964396, PMID: 37682528), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Nov 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 C382R cholangiocarcinoma no benefit Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) did not decrease viability of a cholangiocarcinoma cell line expressing FGFR2 C382R in culture (PMID: 37964396). 37964396
FGFR2 K545del cholangiocarcinoma no benefit Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) did not decrease viability of a cholangiocarcinoma cell line expressing FGFR2 K545del in culture (PMID: 37964396). 37964396
FGFR2 H167_N173del cholangiocarcinoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) decreased viability of a cholangiocarcinoma cell line expressing FGFR2 H167_N173del in culture (PMID: 37964396). 37964396
FGFR2 N631_M640del cholangiocarcinoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) decreased viability of a cholangiocarcinoma cell line expressing FGFR2 N631_M640del in culture (PMID: 37964396). 37964396
FGFR2 I548Wfs*8 cholangiocarcinoma sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) decreased viability of a cholangiocarcinoma cell line expressing FGFR2 I548Wfs*8 in culture (PMID: 37964396). 37964396
FGFR2 I288_D304del cholangiocarcinoma no benefit Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) did not decrease viability of a cholangiocarcinoma cell line expressing FGFR2 I288_D304del in culture (PMID: 37964396). 37964396