选择性剪接事件在子宫内膜癌预后中的作用  

Role of alternative splicing events in endometrial cancer prognosis

作　　者：刘佳婧 米春梅[1] 龙文昕 孙涛 LIU Jiajing;MI Chunmei;LONG Wenxin;SUN Tao(Department of Gynecology,Third Xiangya Hospital,Central South University,Changsha 410013,China)

机构地区：[1]中南大学湘雅三医院妇产科,长沙410013

出　　处：《中南大学学报（医学版）》2021年第7期680-688,共9页Journal of Central South University ：Medical Science

摘　　要：目的:选择性剪接(alternative splicing,AS)是一种强大而普遍的转录调控机制,可以扩大基因组的编码能力。越来越多的证据表明mRNA前体的剪接失调可能与各种类型的癌症有一定的相关性。本研究探究AS在子宫内膜癌(endometrial cancer,EC)预后中的作用。方法:通过对癌症基因组图谱(the Cancer Genome Atlas,TCGA)数据库中配对的EC及其癌旁组织的拼接百分比(percent spliced in,PSI)值筛选出差异性表达AS(differently expressed AS,DEAS)事件,并对其亲本基因进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)分析。用单因素Cox分析筛选出与预后相关的AS事件,并进行多因素Cox回归分析进一步构建Cox预后模型,通过受试者工作特征(receiver operating characteristic,ROC)曲线评价预后模型的诊断价值。最后,构建模型中AS事件与剪切因子的调控网络。结果:在EC中共检测到28281个AS事件,其中存在42个DEAS事件,其亲本基因参与了EC减数分裂核分裂、α−氨基酸生物合成过程以及核分裂等肿瘤相关过程。单因素Cox分析鉴定出2289个与预后相关的AS事件,构建了基于7种不同类型AS事件和包含所有类型AS事件的Cox预后模型,其中包含所有类型AS事件模型的ROC曲线下面积高达0.882,优于其他7种不同类型的模型。有12个剪切因子和AS事件表现出明显的调控关系。结论:利用AS事件的全基因组分析证明了有数千个AS事件与EC显著相关,涉及多个基因,这些基因的剪接在癌症的发展中起至关重要的作用;本研究通过这些AS事件为EC患者建立科学的预后预测模型,为EC临床预后评估提供了可靠的理论依据。Objective:Alternative splicing(AS),as a potent and pervasive mechanism of transcriptional regulation,can expand the genome’s coding capacity.Growing evidence suggests that the AS events may be associated with various types of cancer.This study aims to explore the prognostic value of AS in endometrial cancer(EC).Methods:Differently expressed AS(DEAS)events were screened by pairing the percent spliced in(PSI)value of tumor and paracancerous tissues in The Cancer Genome Atlas(TCGA)database,and gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)were performed on their parental gene analysis of organisms.Subsequently,univariate Cox analysis was used to identify the prognostic AS events and a stepwise multi-factor Cox regression analysis was performed to further construct prognostic models.Furthermore,the diagnostic value of the prognostic model was evaluated by receiver operating characteristic(ROC)curve and Kaplan-Meier analysis.Finally,the regulatory network of AS events and splicing factory in the model was also constructed.Results:A total of 28281 AS events were detected in EC.Of them,42 DEAS were identified,and their parental genes were involved in tumor-related processes such as meiotic nuclear division,alpha-amino acid biosynthetic process,nuclear division,and so on.Univariate Cox analysis identified 2289 prognostic-related AS events and constructed Cox prognostic models based on 7 different types and all types of AS events,in which the area under the curve of ROC of all types was as high as 0.882 and was better than that of 7 different splicing types.Finally,12 splicing factors and AS events showed an obvious regulatory relationship.Conclusion:We use the whole genome analysis of AS events to establish a scientific prognostic prediction model for EC patients,which provides a reliable theoretical basis for the evaluation of EC clinical prognosis.

关 键 词：选择性剪接事件 差异性表达剪接事件 子宫内膜癌 预后模型 

分 类 号：R737.33[医药卫生—肿瘤]