Pediatric KIT-wild-type and platelet-derived growth factor receptor α-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors
Pediatric KIT-wild-type and platelet-derived growth factor receptor α-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors
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DOI：
10.1158/0008-5472.can-07-1938
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Fletcher, Jonathan A.
中科院分区：
文献类型：
--
作者：
Janeway, Katherine A.;Liegl, Bernadette;Fletcher, Jonathan A.
儿童患者中不到15%的胃肠道间质瘤（GIST）携带JUT或血小板衍生生长因子受体α（PDGFRA）突变，而成人GIST的突变率为80%。然而，KIT的一些治疗性抑制剂对儿童GIST有效，这表明KIT可能在肿瘤发生中发挥重要作用。在成人GIST中，特征性细胞遗传学变化发生在恶性进展过程中。更好地了解儿童GIST的遗传进展机制以及KIT和PDGFRA转化作用可能有助于治疗进展。对27例儿童GIST进行了KIT和PDGFRA突变分析。确定KIT、PDGFRA和下游信号中间体的激活状态，并通过单核苷酸多态性分析确定染色体畸变。在11%的儿童GIST中发现了KIT或PDGFRA突变。KIT和信号中间体AKT和丝裂原活化蛋白激酶在儿科GIST中被激活。特别是，大多数儿童KIT野生型GIST显示KIT激活水平与成人JUT突变型GIST相似。儿童JUT野生型GIST缺乏在成人JUT突变型GIST中观察到的典型细胞遗传学缺失。值得注意的是，大多数儿童KIT-野生型GIST进展为恶性肿瘤而不获得大规模染色体畸变，这是以前在恶性实体瘤中未报道的现象。儿童JUT野生型GIST中的KIT活化水平与KIT突变型GIST中的KIT活化水平相当。应在儿科KIT野生型GIST中探索抑制KIT激活或关键KIT信号中间体的治疗方法。
Fewer than 15% of gastrointestinal stromal tumors (GIST) in pediatric patients harbor JUT or platelet-derived growl factor receptor alpha (PDGFRA) mutations in contrast to a mutation rate of 80% in adult GISTs. However, some therapeutic inhibitors of KIT have efficacy in pediatric GIST, suggesting that KIT may, nevertheless, play an important role in oncogenesis. In adult GIST, characteristic cytogenetic changes occur during progression to malignancy. A better understanding of mechanisms of genetic progression and KIT and PDGFRA transforming roles in pediatric GIST might facilitate treatment advances. KIT and PDGFRA mutation analysis was done in 27 pediatric GISTs. The activation status of KIT, PDGFRA, and downstream signaling intermediates was defined, and chromosomal aberrations were determined by single nucleotide polymorphism assays. Mutations in KIT or PDGFRA were identified in 11% of pediatric GISTs. KIT and the signaling intermediates AKT and mitogen-activated protein kinase were activated in pediatric GISTs. In particular, most pediatric KIT-wild-type GISTs displayed levels of KIT activation similar to levels in adult JUT-mutant GISTs. Pediatric JUT-wild-type GISTs lacked the typical cytogenetic deletions seen in adult JUT-mutant GISTs. Notably, most pediatric KIT-wild-type GISTs progress to malignancy without acquiring large-scale chromosomal aberrations, which is a phenomenon not reported previously in malignant solid tumors. KIT activation levels in pediatric JUT-wild-type GISTs are comparable with those in KIT-mutant GISTs. Therapies that inhibit KIT activation, or crucial KIT signaling intermediates, should be explored in pediatric KIT-wild-type GIST.