期刊
CLINICAL CANCER RESEARCH
卷 21, 期 21, 页码 4935-4946出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-2744
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资金
- Federal Ministry of Education and Research (BMBF), Germany
- German Cancer Consortium (DKTK)
- Else-Kroner-Fresenius Stiftung [2013_A49]
- Wilhelm-Sander Stiftung [2009.901.2]
- Deutsche Forschungsgemeinschaft, DFG [MU1328/9-1, MU1328/9-2, MU 1328-14-1]
- EXC 1003 Cells in Motion-Cluster of Excellence, Munster, Germany
- Deutsche Krebshilfe [DKH-108128]
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. (C) 2015 AACR.
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