Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas
Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas
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DOI：
10.1016/j.prp.2006.12.005
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发表时间：
2007-01-01
影响因子：
2.8
通讯作者：
Park, Yong-Koo
中科院分区：
文献类型：
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作者：
Do, Ingu;Araujo, Eduard Santini;Park, Yong-Koo
伊文肉瘤是一种高度恶性的骨肿瘤，好发于儿童和年轻人。尽管使用多模式治疗方法，其5年生存率仅为50%，需要寻找新的治疗靶点并开发新的治疗方式。KIT和PDGFR是III型受体酪氨酸激酶，c-kit（编码KIT）和PDGFR中的激活突变已被报道为许多恶性肿瘤中的致癌事件。伊马替尼是KIT、PDGFR和ABL酪氨酸激酶活性的选择性抑制剂，并根据e-kit和PDGFR基因突变的区域发挥不同的抗肿瘤作用。因此，我们评估了71例福尔马林固定、石蜡包埋的尤文肉瘤中KIT蛋白的免疫组织化学表达以及c-kit基因外显子9、11、13和17、PDGFPA基因外显子12和18以及PDGFRB基因外显子12的突变状态，以增加我们对潜在的（如果有的话）尤文肉瘤的理解。伊马替尼治疗这种恶性肿瘤在71例样本中，27例（38%）为KIT免疫化学阳性;然而，在71例尤文肉瘤中仅2例（2.6%）在外显子9内发现c-kit激活突变。没有激活突变的PDGFRA和PDGFRB基因被发现，但多态性被确定在PDGFPA基因的外显子18。KIT蛋白表达的结果与以前的研究结果一致。这是迄今为止尤文肉瘤中最大的c-kit突变分析系列，结果明确表明，在大多数样本中，尤文肉瘤中e-kit激活突变与KIT蛋白表达不一致。这些发现暗示了KIT活性的其他机制，并留下了imatimb是否能有效治疗尤文肉瘤的问题。(c)2007年，Elsevier GmbH。All rights reserved.
Ewine sarcoma is a highly malignant tumor of bone preferentially arising in children and young adults. Its 5-year survival rate is only 50% despite the use of multimodal therapeutic approaches, requiring a search for new therapeutic targets and the development of novel therapeutic modalities. KIT and PDGFRs are type III receptor tyrosine kinases, and activating mutations in c-kit (which encodes KIT) and PDGFRs have been reported as oncogenic events in many malignancies. Imatinib is a selective inhibitor of KIT, PDGFR, and ABL tyrosine kinase activity and exerts different anti-tumor effects according to the regions of mutations in e-kit and PDGFR genes. Thus, we evaluated the immunohistochemical expression of KIT protein and the mutational status of exons 9, 11, 13, and 17 of the c-kit gene, exons 12 and 18 of the PDGFPA gene, and exon 12 of the PDGFRB gene in 71 formalin-fixed, paraffin-embedded Ewing sarcomas to increase our understanding of the potential, if any.. of imatinib treatment for this malignancy. Of the 71 samples, 27 (38%) were immunohistochemically positive for KIT; however, activating mutations in c-kit were found in only 2 of 71 Ewing sarcomas (2.6%) within exon 9. No activating mutations in the PDGFRA and PDGFRB genes were found, but pleomorphism was identified in exon 18 of the PDGFPA gene. Our results for KIT protein expression agree with those of previous studies. This is the largest series of c-kit mutational analysis in Ewing sarcoma to date, and the results definitively show that e-kit activating mutations are not coincident with KIT protein expression in Ewing sarcoma in most samples. These findings imply other mechanisms for KIT activity and leave open the question of whether imatimb would be efficacious in the treatment of Ewing sarcoma. (c) 2007 Elsevier GmbH. All rights reserved.