基于数据库的未分化甲状腺癌基因组变异分析及靶向药物筛选

Database analysis of genome variations and targeted drug screening of anaplastic thyroid cancers

目的:对未分化甲状腺癌的基因组变异情况进行分析并以此为基础筛选候选靶向药物。方法:通过cBioPortal数据库获得患者样本数据,筛选同时发生突变与拷贝数变异的基因,计算其遗传变异频率。绘制生存曲线以筛选与患者生存率关系密切的基因变异。利用STRING数据库分析蛋白质相互作用并进行GO功能富集分析,利用CARE软件筛选潜在的靶向药物。结果:TP53、PI3KCA、ARID2是未分化甲状腺癌遗传变异频率最高的基因。TP53基因的错义突变与患者生存率下降有关。GO功能富集分析发现P53通过调控DNA损伤修复、细胞周期阻滞等生物学过程参与未分化甲状腺癌的发生。对于携带TP53错义突变的患者,索拉非尼、鲁索替尼等药物具有高反应性,而普纳替尼等药物具有耐药性。结论:TP53基因错义突变是影响未分化甲状腺癌患者预后的关键基因变异,而索拉非尼、鲁索替尼等药物是携带TP53基因错义突变患者的候选靶向药物。

OBJECTIVE:To mind databases for genome variations of anaplastic thyroid cancers and for screening targeted drugs that may be effective on anaplastic thyroid cancers.METHODS:The cBioPortal database for anaplastic thyroid cancer was used to search for the genes with mutations and copy number variations,and to calculate their genetic variation frequencies.The data were also used to draw survival curves and to identify gene variants that were closely related to patients'survival,to analyze protein interactions,to perform GO enrichment using the STRING database,and to screen potential targeted drugs using the CARE software.RESULTS:The database show that TP53,PI3KCA,ARID2 were the genes with the highest frequencies of genetic variation in anaplastic thyroid cancer.In addition,missense mutations in the TP53 gene were related to the decline in patient survival.GO enrichment analyses show that TP53 participated in the pathogenesis of anaplastic thyroid cancer by regulating biological processes such as DNA damage repair and cell cycle arrest.For the patients with the missense mutations in the TP53 gene,they were sensitive to treatment with Sorafenib,Lapatinib,Ruxotinib and other drugs,but were resistant to Ponatinib and other drugs.CONCLUSION:Missense mutations in the TP53 gene were the key gene variations which affected prognosis of patients with anaplastic thyroid cancer.In addition,Sorafenib and Ruxotinib might be candidate drugs which targeted patients with the missense mutations in the TP53 gene.