Site-dependent differential KIT and PDGFRA expression in gastric and intestinal gastrointestinal stromal tumors
Site-dependent differential KIT and PDGFRA expression in gastric and intestinal gastrointestinal stromal tumors
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DOI：
10.1038/modpathol.3800947
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发表时间：
2007-10-01
期刊：
影响因子：
7.5
通讯作者：
Fuezesi, Laszlo
中科院分区：
文献类型：
--
作者：
Haller, Florian;Happel, Nicole;Fuezesi, Laszlo
在胃肠道间质瘤（GIST）中，KIT和PDGFRA相互排斥的功能获得性突变与不同的突变依赖性临床行为相关。考虑到众所周知的不同的临床行为的GIST从胃或肠，目前的研究的目的是评估突变和位点依赖性的影响的mRNA和蛋白质表达的KIT和PDGFRA在一个大系列的主要GIST。采用直接测序法对53例胃（75%）或肠（25%）原发性GIST的新鲜冷冻组织进行KIT或PDGFRA突变分析。此外，KIT和PDGFRA mRNA和蛋白质表达采用定量RT-PCR和定量光密度评估的Western印迹数据进行测定。每个肿瘤都有KIT（79%）或PDGFRA（21%）突变。所有PDGFRA突变的GIST均来自胃部位。与PDGFRA突变的GIST相比，突变依赖性地，KIT突变的GIST具有显著更高的KIT表达，同时显著更低的PDGFRA表达。位点依赖性地，胃GIST具有显著更高的PDGFRA表达和显著更低的KIT表达相比，肠GIST。此外，即使单独考虑KIT突变的GIST，也可以在胃肿瘤中观察到PDGFRA的表达显著高于肠肿瘤。我们还发现PDGFRA的高蛋白表达与较长的无病生存期之间存在显著相关性。胃部位和PDGFRA突变与更高的PDGFRA表达和更长的无病生存期的相关性表明KIT和PDGFRA基因表达对细胞增殖控制的不同调节作用，从而对临床行为产生影响。PDGFRA在胃GIST中的高表达可能有助于众所周知的部位依赖性临床行为。
In gastrointestinal stromal tumors (GISTs), mutually exclusive gain-of-function mutations of KIT and PDGFRA are associated with different mutation-dependent clinical behavior. Taking into account the well-known different clinical behavior of GISTs from the stomach or the intestine, the aim of the current study is to evaluate the mutation-and site-dependent effects on mRNA and protein expression of KIT and PDGFRA in a large series of primary GISTs. Fresh-frozen tissue of 53 primary GISTs from gastric (75%) or intestinal (25%) sites were analyzed for mutation of KIT or PDGFRA using direct sequencing. Furthermore, KIT and PDGFRA mRNA and protein expression were determined using quantitative RT-PCR and quantitative densitometric evaluation of Western blot data. Each tumor either had a mutation of KIT (79%) or PDGFRA (21%). All GISTs with PDGFRA mutation were from gastric sites. Mutation-dependently, GISTs with KIT mutation had a significantly higher expression of KIT and at the same time a significantly lower expression of PDGFRA compared to GISTs with PDGFRA mutation. Site-dependently, gastric GISTs had a significantly higher expression of PDGFRA and a significantly lower expression of KIT compared to intestinal GISTs. Additionally, even if the KIT-mutated GISTs alone were considered, a significantly higher expression of PDGFRA could be observed in gastric than in intestinal tumors. We also found a significant correlation between a higher protein expression of PDGFRA and longer disease-free survival. The correlation of gastric site and PDGFRA mutation with higher PDGFRA expression and longer disease-free survival suggests different regulatory roles of KIT and PDGFRA gene expression on the control of cell proliferation, and, thereby on clinical behavior. The higher PDGFRA expression in gastric GISTs possibly contributes to the well-known site-dependent clinical behavior.