Deep sequencing in conjunction with expression and functional analyses reveals activation of FGFR1 in Ewing sarcoma

Konstantin Agelopoulos, Günther H.S. Richter, Eva Schmidt, Uta Dirksen, Kristina Von Heyking, Benjamin Moser, Hans Ulrich Klein, Udo Kontny, Martin Dugas, Kathrin Poos, Eberhard Korsching, Thorsten Buch, Matthias Weckesser, Isabell Schulze, Regina Besoke, Anika Witten, Monika Stoll, Gabriele Köhler, Wolfgang Hartmann, Eva WardelmannClaudia Rossig, Daniel Baumhoer, Heribert Jürgens, Stefan Burdach, Wolfgang E. Berdel, Carsten Müller-Tidow

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: FGFR1 may constitute a promising target for novel therapeutic approaches in Ewing sarcoma.

Original languageEnglish
Pages (from-to)4935-4946
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number21
DOIs
StatePublished - 1 Nov 2015

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