Deep sequencing in conjunction with expression and functional analyses reveals activation of FGFR1 in ewing sarcoma
| Autor: | Carsten Müller-Tidow, Eberhard Korsching, Daniel Baumhoer, Anika Witten, Udo Kontny, Kristina von Heyking, Regina Besoke, Hans-Ulrich Klein, Martin Dugas, Heribert Jürgens, Matthias Weckesser, Wolfgang E. Berdel, Stefan Burdach, Konstantin Agelopoulos, Günther H.S. Richter, Gabriele Köhler, Wolfgang Hartmann, Uta Dirksen, Eva Schmidt, Thorsten Buch, Monika Stoll, Isabell Schulze, Claudia Rossig, Eva Wardelmann, Kathrin Poos, Benjamin Moser |
|---|---|
| Přispěvatelé: | University of Zurich, Richter, Günther H S |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Cancer Research Mutation rate Adolescent DNA Copy Number Variations 610 Medicine & health Sarcoma Ewing Biology Deep sequencing Transcriptome Young Adult Gene Frequency Cell Line Tumor medicine Animals Humans 10239 Institute of Laboratory Animal Science 1306 Cancer Research Receptor Fibroblast Growth Factor Type 1 Child Gene Exome sequencing Neoplasm Staging Whole genome sequencing Mice Knockout Fibroblast growth factor receptor 1 Gene Expression Profiling High-Throughput Nucleotide Sequencing medicine.disease Molecular biology Gene Expression Regulation Neoplastic Disease Models Animal Oncology Mutation 570 Life sciences biology 590 Animals (Zoology) Female 2730 Oncology Sarcoma Neoplasm Recurrence Local Signal Transduction |
| Popis: | 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. Clin Cancer Res; 21(21); 4935–46. ©2015 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|