Subramanian Subbaya, West Robert B, Corless Christopher L, Ou Wenbin, Rubin Brian P, Chu Kent-Man, Leung Suet Yi, Yuen Siu Tsan, Zhu Shirley, Hernandez-Boussard Tina, Montgomery Kelli, Nielsen Torsten O, Patel Rajiv M, Goldblum John R, Heinrich Michael C, Fletcher Jonathan A, van de Rijn Matt
Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
Oncogene. 2004 Oct 14;23(47):7780-90. doi: 10.1038/sj.onc.1208056.
Most GISTs require oncogenic activation of the KIT or PDGFRA receptor tyrosine kinase proteins, and the genomic mechanisms of oncogene activation are heterogeneous. Notably, the kinase mutation type correlates with both tumor biology and imatinib response. For example, GISTs with KIT exon 11 mutations are typically gastric and have excellent imatinib response, whereas those with KIT exon 9 mutations generally arise in the small bowel and are less responsive to imatinib. To identify genes that might contribute to these biological differences, we carried out gene expression profiling of 26 GISTs with known KIT and PDGFRA mutational status. Expression differences were then evaluated further by RNA in situ hybridization, immunohistochemistry, and immunoblotting. Unsupervised hierarchical clustering grouped tumors with similar mutations together, but the distinction between the different groups was not absolute. Differentially expressed genes included ezrin, p70S6K, and PKCs, which are known to have key roles in KIT or PDGFRA signaling, and which might therefore contribute to the distinctive clinicopathological features in GISTs with different mutation types. These gene products could serve as highly selective therapeutic targets in GISTs containing the KIT or PDGFRA mutational types with which they are associated.
大多数胃肠道间质瘤（GIST）需要KIT或血小板衍生生长因子受体α（PDGFRA）受体酪氨酸激酶蛋白的致癌激活，并且致癌基因激活的基因组机制是异质性的。值得注意的是，激酶突变类型与肿瘤生物学及伊马替尼反应均相关。例如，具有KIT外显子11突变的GIST通常发生于胃，对伊马替尼反应良好，而具有KIT外显子9突变的GIST一般发生于小肠，对伊马替尼反应较差。为了鉴定可能导致这些生物学差异的基因，我们对26例已知KIT和PDGFRA突变状态的GIST进行了基因表达谱分析。然后通过RNA原位杂交、免疫组织化学和免疫印迹进一步评估表达差异。无监督分层聚类将具有相似突变的肿瘤聚集在一起，但不同组之间的区分并非绝对。差异表达基因包括埃兹蛋白、p70核糖体蛋白S6激酶（p70S6K）和蛋白激酶C（PKC），已知它们在KIT或PDGFRA信号传导中起关键作用，因此可能导致不同突变类型GIST具有独特的临床病理特征。这些基因产物可作为与其相关的含有KIT或PDGFRA突变类型的GIST中的高度选择性治疗靶点。
