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• W4361946107 abstract "<div>Abstract<p><b>Purpose:</b> 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 <i>EWS/ETS</i> 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.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> Relapsed tumors consistently showed a 2- to 3-fold increased number of mutations. We identified several recurrently mutated genes at low frequency (<i>ANKRD30A, CCDC19, KIAA0319, KIAA1522, LAMB4, SLFN11, STAG2, TP53, UNC80, ZNF98</i>). An oncogenic fibroblast growth factor receptor 1 (<i>FGFR1</i>) mutation (N546K) was detected, and the <i>FGFR1</i> 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.</p><p><b>Conclusions:</b> FGFR1 may constitute a promising target for novel therapeutic approaches in Ewing sarcoma. <i>Clin Cancer Res; 21(21); 4935–46. ©2015 AACR</i>.</p></div>" @default.
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• W4361946107 date "2023-03-31" @default.
• W4361946107 modified "2023-10-08" @default.
• W4361946107 title "Data from Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma" @default.
• W4361946107 doi "https://doi.org/10.1158/1078-0432.c.6524157" @default.
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