摘要
目的分析甲状腺癌的可变剪切(AS)事件,探讨AS事件与甲状腺癌预后的相关性,并建立AS事件与剪接因子(SF)的调控网络。方法分别从癌症基因图谱(TCGA)和TCGA SpliceSeq数据库下载507例甲状腺癌患者临床资料和AS事件数据,合并得到AS事件生存数据的矩阵,评估7种AS事件的发生情况。采用单因素Cox回归分析筛选与预后相关的AS事件,最小绝对值收敛和选择算子(LASSO)回归分析筛选变量避免模型过度拟合,多因素Cox回归分析构建预后模型。Kaplan-Meier曲线和受试者工作特征(ROC)曲线对预后模型的价值和效能进行评价。利用Pearson试验分析AS事件与SF的相关性,并对SF基因进行GO富集和KEGG通路分析。结果本研究共纳入507例甲状腺癌患者,研究发现10447个基因发生了45150次可变剪切事件。其中ES为主要类型(38.84%),ME发生次数最少(0.51%)。单因素Cox回归筛选出1842个与预后相关的AS事件,多因素Cox分析建立了基于USHBP1-48249-AA、CACNB1-40626-AT和BEX5-89679-AP的预后风险模型。以风险分数0.807为最佳临界值,能够很好地区分高风险和低风险组(P<0.001,AUC=0.929)。构建的SF-AS调控网络中发现多个关键SF基因能够调控AS事件的表达,包括CDK12、RBM25、DDX39B、SRRM2和DDX46等。结论基于3-AS事件的模型对于评估患者预后具有较高的价值,构建的SF-AS调控网络为探讨甲状腺癌发生发展机制提供了新的思路。
Objective To analyze the alternative splicing(AS)events of patients with thyroid carcinoma(THYC)and explore the correlation between AS events and the prognosis of THYC.Methods The clinical data and the Percent Splice In(PSI)value of AS events of THYC were downloaded from The Cancer Gene Atlas(TCGA)database and the TCGA SpliceSeq database respectively.The occurrence of seven kinds of AS events including AA,AD,AF,AP,ME,ES and RI in THYC was investigated and the matrix of AS events and survival data was constructed.Univariate Cox regression analysis was used to screen AS events related to prognosis of THYC.To avoid over-fitting,the least absolute shrinkage and selection operator(LASSO)regression analysis was performed.Then Multivariate Cox regression analysis was used to construct prognosis model.Kaplan-Meier curve and receiver operating characteristic(ROC)curve were performed to evaluate the prognosis ability of the risk model.We also used Pearson correlation analysis to select splicing factors(SF)which were correlated with survival associated AS events.Above SF genes were enrolled to gene ontology(GO)enrichment and KEGG pathway analysis.Results A total of 10447 genes and 45150 AS events in 507 THYC patients were found in the present study.Among them,ES was the main type(38.84%)and ME was the type with the least frequency(0.51%).Totally 1842 AS events associated with prognosis of THYC patients were identified.Three AS events including USHBP1-48249-AA、CACNB1-40626-AT and BEX5-89679-AP were selected to construct the prognosis model.The risk score of 0.807 was indicated as the best cut-off value of prognosis model.The patients were divided into high-risk group(240 cases)and low-risk group(241 cases)based on the risk score.The results demonstrated that the risk model could be used as a valuable prognostic factor for THYC(P<0.001,AUC=0.929).The SF-AS network was constructed and several SF genes,including CDK12,RBM25,DDX39B,SRRM2 and DDX46 were identified as hub genes.Conclusions The risk model based on 3-AS events was
作者
刘英杰
张守彩
岳聪博
季健
郑桂喜
Liu Yingjie;Zhang Shoucai;Yue Congbo;Ji Jian;Zheng Guixi(Department of Clinical Laboratory,Qilu Hospital of Shandong University,Jinan 250012,China;Clinical Laboratory of Qingdao Women and Children's Hospital Affiliated to Qingdao University,Qingdao 266034,China)
出处
《中华检验医学杂志》
CAS
CSCD
北大核心
2022年第11期1163-1169,共7页
Chinese Journal of Laboratory Medicine
基金
国家自然科学基金(82172347)
山东省重点研发计划(2019GSF108064)。
关键词
甲状腺肿瘤
可变剪切事件
剪接因子
预后
Thyroid neoplasms
Alternative splicing event
Splicing factor
Prognosis
