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

K Agelopoulos, GHS Richter, E Schmidt, U Dirksen… - Clinical Cancer …, 2015 - AACR
K Agelopoulos, GHS Richter, E Schmidt, U Dirksen, K von Heyking, B Moser, HU Klein
Clinical Cancer Research, 2015AACR
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 …
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. Clin Cancer Res; 21(21); 4935–46. ©2015 AACR.
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