Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma
Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma
复制标题
DOI：
10.1158/1078-0432.ccr-14-2744
复制
发表时间：
2015-11-01
影响因子：
11.5
通讯作者：
Mueller-Tidow, Carsten
中科院分区：
文献类型：
--
作者：
Agelopoulos, Konstantin;Richter, Guenther H. S.;Mueller-Tidow, Carsten
目的：低突变率似乎是儿科癌症的普遍特征，特别是在肿瘤融合基因驱动的肿瘤中。在遗传学上，尤文肉瘤是由平衡的染色体EWS/ETS易位定义的，其产生致癌嵌合蛋白（EWS-ETS）。其他参与疾病发展的体细胞突变只在低frequency.Experimental设计观察到：116尤文肉瘤患者的肿瘤样本进行了分析。对两名正常、原发和复发组织的患者进行全基因组测序。对50例尤文肉瘤和22例匹配的正常组织进行全外显子组测序。这些肿瘤/正常对中的14个的发现数据集鉴定了232个体细胞突变。在剩余的36个外显子组中验证了复发性非同义突变。转录组分析进行了50尤文肉瘤和DNA拷贝数的增益和FGFR 1的表达在63 116尤文sarcomas.Results：复发的肿瘤始终表现出2至3倍的突变数量增加的一个子集。我们鉴定了几个低频率的复发突变基因（ANKRD 30 A、CCDC 19、KIAA 0319、KIAA 1522、LAMB 4、SLFN 11、STAG 2、TP 53、UNC 80、ZNF 98）。检测到致癌成纤维细胞生长因子受体1（FGFR 1）突变（N546 K），并且FGFR 1基因座在原发性肿瘤中经常显示拷贝数增加（31.7%）。此外，高水平的FGFR 1表达被认为是尤文肉瘤的一个特征。RNA干扰尤文肉瘤细胞系中FGFR 1的表达阻断了增殖并完全抑制了异种移植肿瘤的生长。FGFR 1酪氨酸激酶抑制剂（TKI）治疗尤文肉瘤复发患者显着降低18-FDG-PET activity.Conclusions：FGFR 1可能构成一个有前途的新的治疗方法在尤文肉瘤的目标。(C)2015年AACR。
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.