Martinho Olga, Gouveia António, Viana-Pereira Marta, Silva Paula, Pimenta Amadeu, Reis Rui Manuel, Lopes José Manuel
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
Histopathology. 2009 Jul;55(1):53-62. doi: 10.1111/j.1365-2559.2009.03323.x.
Gastrointestinal stromal tumours (GISTs) are commonly driven by oncogenic mutations in KIT and PDGFRA. However, 10-40% of these patients are wild-type for these genes. The prognostic significance of wild-type GISTs is controversial, and they rarely respond to imatinib. The aim of this study was to elucidate the molecular lesions underlying wild-type GISTs tumorigenesis.
Twenty-nine KIT and PDGFRA wild-type GISTs were re-assessed for the presence of 'cryptic'KIT exon 11 duplications. Using a specific polymerase chain reaction assay, three previously undetected mutations were identified. In the remaining 26 wild-type GISTs, KIT, stem cell factor (SCF), phospho-KIT and phospho-ERK expression was evaluated by immunohistochemistry. Samples were screened for gain-of-function mutations in the mitogen-activated protein kinase (MAPK) cascade. KIT and SCF co-expression associated with KIT activation was observed in approximately 30% of cases. Furthermore, phospho-ERK expression showed that MAPK is activated in approximately 30% of cases. None of RAS family (H-, K- and N-RAS) oncogenes exhibited activating mutations, whereas BRAF mutations were found in approximately 4% of cases.
In the absence of RAS mutations, MAPK could be activated through SCF/KIT autocrine/paracrine mechanisms and/or mutated BRAF in a subset of KIT/PDGFRA wild-type GISTs.
胃肠道间质瘤（GISTs）通常由KIT和血小板衍生生长因子受体α（PDGFRA）的致癌突变驱动。然而，这些患者中有10%-40%的人这些基因是野生型的。野生型GISTs的预后意义存在争议，并且它们对伊马替尼很少有反应。本研究的目的是阐明野生型GISTs肿瘤发生的分子病变。
对29例KIT和PDGFRA野生型GISTs重新评估是否存在“隐匿性”KIT外显子11重复。使用特异性聚合酶链反应检测，鉴定出3个先前未检测到的突变。在其余26例野生型GISTs中，通过免疫组织化学评估KIT、干细胞因子（SCF）、磷酸化KIT和磷酸化细胞外信号调节激酶（ERK）的表达。对丝裂原活化蛋白激酶（MAPK）级联中的功能获得性突变进行样本筛查。在约30%的病例中观察到KIT和SCF共表达与KIT激活相关。此外，磷酸化ERK表达显示MAPK在约30%的病例中被激活。RAS家族（H-RAS、K-RAS和N-RAS）致癌基因均未表现出激活突变，而约4%的病例中发现BRAF突变。
在缺乏RAS突变的情况下，MAPK可通过SCF/KIT自分泌/旁分泌机制和/或在一部分KIT/PDGFRA野生型GISTs中突变的BRAF被激活。
