Identification of Targetable FGFR Gene Fusions in Diverse Cancers

By Yi-Mi Wu, Fengyun Su, Shanker Kalyana-Sundaram, N. Khazanov, Bushra Ateeq, Xuhong Cao, R. Lonigro, P. Vats, Rui Wang, Su-Fang Lin and 15 more. Cancer Discovery, 2013

689 citations recorded by the source corpus.

Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2 including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR gene fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/792ea13f08f6a57033387c817bd8d0f2a94ec68d

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Citations in the corpus

FusionCatcher – a tool for finding somatic fusion genes in paired-end RNA-sequencing data (2014, background): “As fusion genes are known to reside on re-arranged areas on the genome, this indicates that the FGFR2 gene is probably a fusion gene partner [11, 14] in these cell lines.”
Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. (2014, background): “Fusions including the kinase domain of FGFR2 have been recently reported [79].”
Mechanisms of receptor tyrosine kinase activation in cancer (2018, neutral): “Second, most fusion partners contribute an oligomerization domain, which promotes ligand independent constitutive activation of the kinase [94, 127, 128].”
Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma (2013, background): “A recent study identified novel FGFR2 gene fusions in CCA.(82) Cells with these FGFR fusions were susceptible to FGFR inhibitors, signifying that FGFR kinase inhibition may be a valid therapeutic strategy in CCA patients harboring these gene fusions.”
Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma (2017, background): “FGFR2 fusion genes, previously reported in CCA (21), are thought to deregulate FGFR2 signalling through the hijacking of 3′ fusion partners with dimerization motifs (21,22).”
Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling (2017, background): “FGF pathway activation has been shown to occur in rare instances by FGFR genomic rearrangements in mCRPC (Wu et al., 2013), but we found no evidence of mutation, copy-number gain, or gene rearrangements involving FGF8 or FGFRs in LNCaPAPIPC (Figures S3B and S3C).”
Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours (2014, background): “FGFR1 IIIc 9 BAG4 2 LUSC 1 [32] FGFR1 4 ERLIN2 10 Breast cancer 1 [32] FGFR1 TACC1 Glioblastoma 1 [13] FGFR2 IIIb 19 BICC1 3 Metastatic cholangiocarcinoma 2 [32] FGFR2 IIIb 17 CIT 23 Lung adenocarcinoma 1 [31] FGFR2 IIIc 19 AFF3 8 Breast cancer 1 [32] FGFR2 IIIc 19 CASP7 4 Breast cancer 1 [32] FGFR2”
Cholangiocarcinoma 2020: the next horizon in mechanisms and management (2020, neutral): “…sequencing studies 56,112–121 and IDH2 R172 ) that cause an accumulation of the onco-metabolite 2-hydroxyglutarate (2-HG) 57 , as well as the constitutive active gene fusion event between FGFR2 and many different partners, including the most prevalent ( BICC1 (reFs 50,112–114 ) , PPHLN1 (reF.”
Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma (2014, neutral): “Creighton(5), Carolyn Smith(8), Broad Institute - David J.”