Molecular characterization of pediatric gastrointestinal stromal tumors
Molecular characterization of pediatric gastrointestinal stromal tumors
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DOI：
10.1158/1078-0432.ccr-07-1984
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发表时间：
2008-05-15
影响因子：
11.5
通讯作者：
Antonescu, Cristina R.
中科院分区：
文献类型：
--
作者：
Agaram, Narasimhan P.;Laquaglia, Michael P.;Antonescu, Cristina R.
目的：儿童胃肠道间质瘤(GIST)是一种少见的多发于女性的多灶性胃肿瘤，通常在KIT和PDGFRA中缺乏突变，由于KIT癌蛋白在儿童GIST中持续过表达，我们试图研究KIT下游靶点的激活和KIT/PDGFRA基因拷贝数的变化，通过基因表达挖掘新的治疗靶点，并通过蛋白质组学检测酪氨酸激酶受体的激活。实验设计：对17例儿童GIST进行KIT/PDGFRA基因分型和KIT下游靶点的生化激活。比较了8例儿童患者的13个结节和8个成人野生型(WT)GIST的转录谱，其中包括3个年轻人。结果：12例女性患者均为KIT/PDGFRA基因突变，而5例男性患者中有2例存在KIT基因外显子11或PDGFRA外显子18突变。KIT下游目标一直被激活。儿科医生表现出明显的转录特征，BAALC PLAG1、IGF1R、FGF4和NELL1过表达。体外研究表明，尼洛替尼、舒尼替尼、达沙替尼和索拉非尼对WT KIT的治疗效果优于伊马替尼。结论：少见的儿童GIST可能发生在男性患者，并且存在KIT/PDGFRA激活突变。儿科医生表现出明显的转录特征，表明成人的GIST与WT GIST不同。体外药物筛选显示，第二代激酶抑制剂可能在儿童GIST中提供更大的临床益处。
Purpose: Pediatric gastrointestinal stromal tumors (GIST) are rare and occur preferentially in females as multifocal gastric tumors, typically lacking mutations in KIT and PDGFRA, As KIT oncoprotein is consistently overexpressed in pediatric GIST, we sought to investigate the activation of KIT downstream targets and alterations of KIT/PDGFRA gene copy number, mine novel therapeutic targets by gene expression, and test tyrosine kinase receptor activation by proteomic profiling.Experimental Design: Seventeen pediatric GISTs were investigated for KIT/PDGFRA genotype and biochemical activation of KIT downstream targets. The transcriptional profile of 13 nodules from 8 pediatric patients was compared with 8 adult wild-type (WT) GISTs, including 3 young adults. The drug sensitivity of second-generation kinase inhibitors was tested in murine Ba/F3 cells expressing human WT KIT, as well as in short-term culture of explants of WT GIST cells.Results: A KIT/PDGFRA WT genotype was identified in all 12 female patients, whereas two of five males had either a KIT exon 11 or PDGFRA exon 18 mutation. KIT downstream targets were consistently activated. Pediatric GISTS showed a distinct transcriptional signature, with overexpression of BAALC PLAG1, IGF1R, FGF4, and NELL1. In vitro studies showed that nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib against WT KIT.Conclusions: Rare cases of pediatric GIST may occur in male patients and harbor activating KIT/PDGFRA mutations. Pediatric GISTS show distinct transcriptional signature, suggesting a different biology than WT GIST in adults. In vitro drug screening showed that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GIST.