Reference Detail

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
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 I548Wfs8 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). I548Wfs8 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 2023).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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 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 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 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 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