纺锤体检测点蛋白BUB1B在三阴型乳腺癌中的表达及意义  

Prognostic values of spindle checkpoint protein BUB1B in triple negative breast cancer

作　　者：张培川 钟晓蓉[2] 郑鸿[2] 李丽[1] 陈菲[1] 申梦佳 李怡洁 陈红[1] 曹师瑜 步宏[3] 叶丰[1] Zhang Peichuan;Zhong Xiaorong;Zheng Hong;Li Li;Chen Fei;Shen Mengjia;Li Yijie;Chen Hong;Cao Shiyu;Bu Hong;Ye Feng(Institute of Clinical Pathology,Key Laboratory of Transplant Engineering and Immunology,Ministry of Health,West China Hospital,Sichuan University,Chengdu 610041,China;Department of Head and Neck Oncology Cancer Center,West China Hospital,Sichuan University,Chengdu 610041,China;Department of Pathology,West China Hospital,Sichuan University,Chengdu 610041,China)

机构地区：[1]四川大学华西医院卫健委移植工程与移植免疫重点实验室,临床病理研究所,成都610041 [2]四川大学华西医院肿瘤中心头颈肿瘤科,成都610041 [3]四川大学华西医院病理科,成都610041

出　　处：《中华病理学杂志》2021年第6期645-649,共5页Chinese Journal of Pathology

基　　金：四川省科技厅计划项目(2017SZ0005);四川大学华西医院学科卓越发展1·3·5工程项目高端人才支持计划(ZYGD18012)。

摘　　要：目的高通量筛选三阴型乳腺癌(triple negative breast cancer,TNBC)预后相关的重要分子标志物,探讨纺锤体检测点蛋白BUB1B表达与TNBC临床病理特征及预后相关性。方法收集2009—2017年四川大学华西医院诊断TNBC的临床病理资料和预后信息。选取符合纳入标准的新鲜样本47例,肿瘤原发灶石蜡样本139例。对新鲜肿瘤样本进行转录组测序(RNA-seq)与基因表达综合数据库(gene expression omnibus,GEO)数据集GSE38959和GSE65194差异分析并取交集,进行富集分析和蛋白相互作用(protein-protein interaction,PPI)分析。利用Kaplan-Meier Plotter数据库分析目的基因的表达水平与TNBC预后的关系。采用免疫组织化学染色验证其在TNBC中的表达情况及与临床病理特征和预后的相关性。结果利用edgeR对47例TNBC肿瘤组织与其中12例正常组织进行差异分析得到1559个上调基因和1376个下调基因,与GEO2R对GSE38959和GSE65194差异分析后的差异基因取交集后得到131个基因。富集分析主要富集在细胞周期、JAK-STAT信号通路、p53信号通路。利用Cytoscape分析得到Degree最高的10个基因:TOP2A、BUB1B、MKI67、PLK1、RRM2、PCNA、KPNA2、SMC4、PBK、IGF1。Kaplan-Meier Plotter数据库中分析发现BUB1B表达与TNBC预后显著相关[总生存期,HR=0.52,95%CI(0.35~0.77),P=0.001;无远处转移生存期,HR=0.72,95%CI(0.52~0.98),P=0.038]。139例肿瘤原发灶石蜡样本免疫组织化学的结果显示BUB1B低表达与TNBC预后不良具有显著相关性[HR=0.41,95%CI(0.18~0.95),P=0.024]。结论BUB1B蛋白低表达与TNBC预后不良相关,其预后相关分子机制和潜在治疗靶点有待进一步研究。Objective To identify important prognostic molecular markers of triple negative breast cancer(TNBC)using high throughput sequencing technology and to explore the correlation of spindle checkpoint protein BUB1B and clinicopathological features with patients′prognosis.Methods The clinicopathological data and prognostic information of TNBC diagnosed at the West China Hospital of Sichuan University from 2009 to 2017 were collected.Forty-seven fresh tumor samples and 139 formalin fixed paraffin-embedded samples were selected.The fresh tumor samples were subject to RNA sequencing(RNA-seq).The enrichment analysis and protein-protein interaction(PPI)analysis were performed after intersection of difference analysis between RNAseq and GEO(Gene Expression Omnibus)datasets GSE38959 and GSE65194.Kaplan-Meier plotter database was used to analyze the relationship between expression of BUB1B and prognosis.Immunohistochemical staining was used to verify its expression in TNBC and correlation with clinicopathological features and prognosis.Results Using edgeR to perform differential expression analysis between 47 TNBC tumor tissues and 12 normal tissues,1559 up-regulated genes and 1376 down-regulated genes were identified,while only 131 differentially expressed genes were overlapping with those in GSE38959 and GSE65194.Enrichment analysis was mainly enriched in cell cycle,JAK-STAT signaling pathway and p53 signaling pathway.The top 10 genes ranked by degree of association were TOP2A,BUB1B,MKI67,PLK1,RRM2,PCNA,KPNA2,SMC4,PBK and IGF1.Kaplan-Meier plotter database analysis showed that the expression of BUB1B was significantly correlated with the prognosis of TNBC[overall survival,hazard ratio(HR)=0.52,95%CI(0.35-0.77),P=0.001;distant metastasis-free,HR=0.72,95%CI(0.52-0.98),P=0.038].The immunohistochemical analyses of 139 formalin fixed paraffin-embedded samples showed that the low expression of BUB1B was correlated with poor prognosis in TNBC[HR=0.41,95%CI(0.18-0.95),P=0.024].Conclusions The low expression of BUB1B protein is ass

关 键 词：乳腺肿瘤 生物学标记 预后 

分 类 号：R737.9[医药卫生—肿瘤]