Reference Detail

Ref Type

Journal Article

PMID

(26179511)

Authors

Agelopoulos K, Richter GH, Schmidt E, Dirksen U, von Heyking K, Moser B, Klein HU, Kontny U, Dugas M, Poos K, Korsching E, Buch T, Weckesser M, Schulze I, Besoke R, Witten A, Stoll M, Köhler G, Hartmann W, Wardelmann E, Rossig C, Baumhoer D, Jürgens H, Burdach S, Berdel WE, Müller-Tidow C

Title

Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	21	21	2015 Nov 01	4935-46	Clin Cancer Res

URL

Abstract Text

A low mutation rate seems to be a general feature of pediatric cancers, in particular in oncofusion gene-driven tumors. Genetically, Ewing sarcoma is defined by balanced chromosomal EWS/ETS translocations, which give rise to oncogenic chimeric proteins (EWS-ETS). Other contributing somatic mutations involved in disease development have only been observed at low frequency.Tumor samples of 116 Ewing sarcoma patients were analyzed here. Whole-genome sequencing was performed on two patients with normal, primary, and relapsed tissue. Whole-exome sequencing was performed on 50 Ewing sarcoma and 22 matched normal tissues. A discovery dataset of 14 of these tumor/normal pairs identified 232 somatic mutations. Recurrent nonsynonymous mutations were validated in the 36 remaining exomes. Transcriptome analysis was performed in a subset of 14 of 50 Ewing sarcomas and DNA copy number gain and expression of FGFR1 in 63 of 116 Ewing sarcomas.Relapsed tumors consistently showed a 2- to 3-fold increased number of mutations. We identified several recurrently mutated genes at low frequency (ANKRD30A, CCDC19, KIAA0319, KIAA1522, LAMB4, SLFN11, STAG2, TP53, UNC80, ZNF98). An oncogenic fibroblast growth factor receptor 1 (FGFR1) mutation (N546K) was detected, and the FGFR1 locus frequently showed copy number gain (31.7%) in primary tumors. Furthermore, high-level FGFR1 expression was noted as a characteristic feature of Ewing sarcoma. RNA interference of FGFR1 expression in Ewing sarcoma lines blocked proliferation and completely suppressed xenograft tumor growth. FGFR1 tyrosine kinase inhibitor (TKI) therapy in a patient with Ewing sarcoma relapse significantly reduced 18-FDG-PET activity.FGFR1 may constitute a promising target for novel therapeutic approaches in Ewing sarcoma.

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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
FGFR1	N546K	missense	gain of function	FGFR1 N546K lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). N546K does not confer a growth advantage in a competition assay (PMID: 34272467), but results in increased Fgfr1 protein nuclear localization, Erk, Akt, and Stat3 phosphorylation (PMID: 35488346), and kinase activity, and is transforming in cultured cells (PMID: 26179511, PMID: 23817572, PMID: 29533785).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 amp	Ewing sarcoma	predicted - sensitive	Ponatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited proliferation of Ewing’s sarcoma cell lines with FGFR1 copy number gain in culture (PMID: 26179511).	26179511