Biology of gastrointestinal stromal tumors
Biology of gastrointestinal stromal tumors
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DOI：
10.1200/jco.2004.05.140
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发表时间：
2004-09-15
影响因子：
45.3
通讯作者：
Heinrich, MC
中科院分区：
文献类型：
--
作者：
Corless, CL;Fletcher, JA;Heinrich, MC
胃肠道间质瘤（GIST）曾经是一种定义不清的病理异常，近年来，胃肠道间质瘤（GIST）已成为一种独特的致癌实体，目前已成为激酶靶向治疗临床试验的中心阶段。这篇综述描绘了GIST作为理解致癌激酶突变在人类肿瘤发生中的作用的模型的快速进展。大约80%到85%的gist含有KIT酪氨酸激酶的激活突变。在作者详细研究的322例gist病例（包括140例先前发表的病例）中，KIT基因突变发生在外显子11（66.1%）、9（13%）、13（1.2%）和17（0.6%）的频率呈下降趋势。在同一系列中，一部分肿瘤在kit相关激酶基因PDGF受体α (PDGFRA)中发生突变，突变发生在外显子18（5.6%）或12（1.5%）。其余的gist（12%）对于KIT和PDGFRA均为野生型。对kit突变型、pdgfr突变型和野生型gist的比较研究表明，这些肿瘤组之间有许多相似之处，但也有重要的差异。特别是，gist对激酶抑制剂伊马替尼治疗的反应性很大程度上取决于KIT或PDGFRA突变的外显子位置。鉴于这些差异对GIST的诊断和治疗都有影响，我们提出了基于分子的GIST分类。最近对家族性GIST、儿科GIST以及与卡尼三联征和1型神经纤维瘤病相关的GIST变异形式的研究讨论了与这种分子分类的关系。此外，本综述还强调了KIT和PDGFRA突变筛查作为诊断和预后辅助手段的作用。
Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney's triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.