Novel SEC61G-EGFR Fusion Gene in Pediatric Ependymomas Discovered by Clonal Expansion of Stem Cells in Absence of Exogenous Mitogens
Novel SEC61G-EGFR Fusion Gene in Pediatric Ependymomas Discovered by Clonal Expansion of Stem Cells in Absence of Exogenous Mitogens
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DOI：
10.1158/0008-5472.can-17-0790
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发表时间：
2017-11-01
期刊：
影响因子：
11.2
通讯作者：
Riccardi, Riccardo
中科院分区：
文献类型：
--
作者：
Servidei, Tiziana;Meco, Daniela;Riccardi, Riccardo
中枢神经系统室管膜瘤分子和细胞异质性的基础尚不清楚。这项研究表明，这种现象的基础上，选择分裂原非依赖性（MI）干细胞样细胞与受损的增殖，但增加颅内致瘤性。通过选择EGF/FGF 2非依赖性增殖创建的MI室管膜瘤细胞系表现出EGFR、AKT和STAT 3的组成性激活，并对EGFR酪氨酸激酶抑制剂（TKI）的抗增殖作用敏感。一个高度致瘤性MI线窝藏膜结合，组成型活性，截短的EGFR。两种EGFR突变体（DN 566和DN 599）被鉴定为染色体内重排的产物，其将EGFR基因的编码部分融合到SEC 61 G的5 '-UTR，产生缺乏受体的整个胞外配体结合结构域同时保留跨膜和酪氨酸激酶结构域的产物。EGFR TKI有效地靶向DN 566/DN 599-突变介导的信号传导，并延长了携带这些突变的MI细胞颅内异种移植物的小鼠的存活期。对16例儿童室管膜瘤样本进行RT-PCR测序，在1例幕下室管膜瘤WHO III中鉴定出SEC 61 G-EGFR嵌合mRNA，认为这种融合发生在这些肿瘤的一小部分中。我们的研究结果证明了应用于遗传异质性肿瘤的体外培养选择如何有助于识别在罕见癌症中可能具有药物作用的局灶性突变。(C)2017年AACR。
The basis for molecular and cellular heterogeneity in ependymomas of the central nervous system is not understood. This study suggests a basis for this phenomenon in the selection for mitogen-independent (MI) stem-like cells with impaired proliferation but increased intracranial tumorigenicity. MI ependymoma cell lines created by selection for EGF/FGF2-independent proliferation exhibited constitutive activation of EGFR, AKT, and STAT3 and sensitization to the antiproliferative effects of EGFR tyrosine kinase inhibitors (TKI). One highly tumorigenic MI line harbored membrane-bound, constitutively active, truncated EGFR. Two EGFR mutants (DN566 and DN599) were identified as products of intrachromosomal rearrangements fusing the 30 coding portion of the EGFR gene to the 5'-UTR of the SEC61G, yielding products lacking the entire extracellular ligand-binding domain of the receptor while retaining the transmembrane and tyrosine kinase domains. EGFR TKI efficiently targeted DN566/DN599-mutant-mediated signaling and prolonged the survival of mice bearing intracranial xenografts of MI cells harboring these mutations. RT-PCR sequencing of 16 childhood ependymoma samples identified SEC61G-EGFR chimeric mRNAs in one infratentorial ependymoma WHO III, arguing that this fusion occurs in a small proportion of these tumors. Our findings demonstrate how in vitro culture selections applied to genetically heterogeneous tumors can help identify focal mutations that are potentially pharmaceutically actionable in rare cancers. (C) 2017 AACR.