癌基因KIT、KRAS突变在鼻咽癌预后中的作用及干预措施

鼻咽癌高发于广东省等华南地区，放化综合治疗是主要治疗手段。但中晚期患者的长期生存仍只有70%，单纯TNM临床分期不能反映不同个体肿瘤生物学异质性。而研究鼻咽癌发生进展的分子机制并给予特异性的靶向治疗，是提高总体生存率的关键。我们的前期工作已发现：鼻咽癌的突变主要集中在KIT、KRAS等10个癌基因，且其突变与预后相关。在此基础上，本课题拟继续开展：①在大样本鼻咽癌中检测同一标本19个常见癌基因，并绘制基因突变谱；外显子测序明确KIT和KRAS基因其他新的突变位点；②体内外实验阐明KIT和KRAS突变在鼻咽癌中的作用和机制，采用组织芯片检测KIT和KRAS及上下游蛋白的表达改变；③体内外实验明确KIT抑制剂法米替尼对鼻咽癌的作用及对放化疗敏感性的影响；开展前瞻性临床试验明确法米替尼联合同期放化疗在局部晚期鼻咽癌的疗效。通过本项目的实施，可为鼻咽癌治疗提供新靶点，为实现"个体化"治疗奠定基础。

The highest incidence of nasopharyngeal carcinoma was found in southeast China, especially in Guangdong province. Radiotherapy and chemotherapy are the main treatments, and the long-term survival rate was only seventy percent in patients with the middle-late stage disease. Therefore, the TNM staging system could not reflect the biological heterogeneity of cancer. Understanding the mechanism of nasopharyngeal carcinoma can provide specific therapy targets and improve the treatment outcome. In our primary study, we identified 10 mutation genes in nasopharyngeal carcinoma using the Sequenom mass array system, which was associated with patients survival. Based on this, we'll conduct studies as follow: (1) Mass spectrometry sequencing was used to detect the gene mutation of 19 oncogenes in a large sample size, and identify the gene mutation spectrum. Exon sequencing was used to identify new mutation sites of KIT and KRAS gene. (2) Stable cell lines expressing KIT/KRAS mutants were established to demonstrate the function and mechanism in vitro and vivo. Tissue array was adopted to detect the KIT and KRAS protein and and other protein expression. (3) Famitinib is a small molecular tyrosine kinase inhibitor targeting KIT and so on, and its function was determined in vitro and vivo. Further, prospective clinical trial was deseign to explore the treatment value of famitinib combined with radiation and chemotherapy in locally advanced nasopharyngeal carcinoma. Through this research implementation, it could provide potential new targets for individual therapy in patients with nasopharyngeal carcinoma.