Zhang P C, Zhong X R, Zheng H, Li L, Chen F, Shen M J, Li Y J, Chen H, Cao S Y, Bu H, Ye F
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.
Zhonghua Bing Li Xue Za Zhi. 2021 Jun 8;50(6):645-649. doi: 10.3760/cma.j.cn112151-20210131-00108.
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. 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. Using edgeR to perform differential expression analysis between 47 TNBC tumor tissues and 12 normal tissues, 1 559 up-regulated genes and 1 376 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% (0.35-0.77), =0.001; distant metastasis-free, HR=0.72, 95% (0.52-0.98), =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% (0.18-0.95), =0.024]. The low expression of BUB1B protein is associated with poor prognosis in TNBC patients, and the molecular mechanism related with prognosis and potential therapeutic targets need to be further studied.
利用高通量测序技术鉴定三阴性乳腺癌（TNBC）重要的预后分子标志物，并探讨纺锤体检查点蛋白BUB1B与临床病理特征及患者预后的相关性。收集2009年至2017年在四川大学华西医院诊断的TNBC的临床病理数据和预后信息。选取47例新鲜肿瘤样本和139例福尔马林固定石蜡包埋样本。对新鲜肿瘤样本进行RNA测序（RNA-seq）。在RNAseq与GEO（基因表达综合数据库）数据集GSE38959和GSE65194之间进行差异分析后，进行富集分析和蛋白质-蛋白质相互作用（PPI）分析。使用Kaplan-Meier plotter数据库分析BUB1B表达与预后的关系。采用免疫组织化学染色验证其在TNBC中的表达及其与临床病理特征和预后的相关性。使用edgeR对47例TNBC肿瘤组织和12例正常组织进行差异表达分析，鉴定出1559个上调基因和1376个下调基因，而与GSE38959和GSE65194中的差异表达基因仅有131个重叠。富集分析主要富集在细胞周期、JAK-STAT信号通路和p53信号通路。按关联度排名前10的基因依次为TOP2A、BUB1B、MKI67、PLK1、RRM2、PCNA、KPNA2、SMC4、PBK和IGF1。Kaplan-Meier plotter数据库分析显示，BUB1B的表达与TNBC的预后显著相关[总生存期，风险比（HR）=0.52，95%（0.35-0.77），P=0.001；无远处转移生存期，HR=0.72，95%（0.52-0.98），P=0.038]。对139例福尔马林固定石蜡包埋样本的免疫组织化学分析显示，TNBC中BUB1B低表达与预后不良相关[HR=0.41，95%（0.18-0.95），P=0.024]。TNBC患者中BUB1B蛋白低表达与预后不良相关，与预后相关的分子机制和潜在治疗靶点有待进一步研究。
