Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma

被引：64

作者：

Agelopoulos, Konstantin ^{[1
]}

Richter, Guenther H. S. ^{[2
,3
,4
,5
]}

Schmidt, Eva ^{[1
]}

Dirksen, Uta ^{[6
]}

von Heyking, Kristina ^{[2
,3
,4
,5
]}

Moser, Benjamin ^{[1
]}

Klein, Hans-Ulrich ^{[7
]}

Kontny, Udo ^{[8
]}

Dugas, Martin ^{[7
]}

Poos, Kathrin ^{[9
]}

Korsching, Eberhard ^{[9
]}

Buch, Thorsten ^{[10
,11
]}

Weckesser, Matthias ^{[12
]}

Schulze, Isabell ^{[1
,13
]}

Besoke, Regina ^{[14
]}

Witten, Anika ^{[15
]}

Stoll, Monika ^{[15
]}

Koehler, Gabriele ^{[16
]}

Hartmann, Wolfgang ^{[17
]}

Wardelmann, Eva ^{[17
]}

Rossig, Claudia ^{[6
]}

Baumhoer, Daniel ^{[18
]}

Juergens, Heribert ^{[6
]}

Burdach, Stefan ^{[2
,3
,4
,5
]}

Berdel, Wolfgang E. ^{[1
]}

Mueller-Tidow, Carsten ^{[1
,13
]}

机构：

[1] Univ Hosp Muenster, Dept Med Hematol & Oncol A, Munster, Germany

[2] Tech Univ Munich, Klinikum Rechts Isar, Childrens Canc Res Ctr, D-80804 Munich, Germany

[3] Tech Univ Munich, Klinikum Rechts Isar, Dept Pediat, D-80804 Munich, Germany

[4] CCCM, Munich, Germany

[5] German Canc Consortium DKTK, Dresden, Germany

[6] Univ Childrens Hosp Muenster, Dept Pediat Oncol & Hematol, Munster, Germany

[7] Univ Munster, Inst Med Informat, Munster, Germany

[8] Rhein Westfal TH Aachen, Fac Med, Dept Pediat, Aachen, Germany

[9] Univ Hosp Muenster, Inst Bioinformat, Munster, Germany

[10] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-80804 Munich, Germany

[11] Univ Zurich, Inst Lab Anim Sci, Zurich, Switzerland

[12] Univ Munster, Dept Nucl Med, Munster, Germany

[13] Univ Hosp Halle, Dept Med Hematol & Oncol 4, State Ctr Cell & Gene Therapy, D-06120 Halle, Saale, Germany

[14] Univ Munster, Inst Human Genet, Munster, Germany

[15] Univ Munster, Inst Human Genet, Genet Epidemiol, Munster, Germany

[16] Klinikum Fulda, Inst Pathol, Fulda, Germany

[17] Univ Munster, Dept Pathol, Munster, Germany

[18] Univ Basel Hosp, Inst Pathol, Bone Tumor Reference Ctr, CH-4031 Basel, Switzerland

来源：

CLINICAL CANCER RESEARCH | 2015年 / 21卷 / 21期

关键词：

CHROMOSOME-TRANSLOCATION; GENOMIC LANDSCAPE; COPY-NUMBER; CANCER; STAG2; INACTIVATION; CHILDHOOD; MUTATIONS; EVOLUTION; BLOCKING;

D O I：

10.1158/1078-0432.CCR-14-2744

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：4935 / 4946

页数：12

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