弥漫大B细胞淋巴瘤预后相关差异表达自噬基因筛选及模型的建立

Screening of Differential Expression Autophagy Genes Related to the Prognosis of Diffuse Large B-Cell Lymphoma and Establishment of an Autophagy Model

目的:筛选弥漫大B细胞淋巴瘤(DLBCL)自噬相关基因(ARG)的差异表达,探讨差异表达自噬基因(DEARG)在DLBCL发生发展中的作用机制并建立预后模型。方法:利用包含481例DLBCL患者临床信息及基因表达谱数据的NCICCR数据库与包含232个ARG的HADb数据库,通过R语言确定DLBCL中ARG的差异表达,GO和KEGG分析ARG与DLBCL发生发展的关系,Cox回归算法建立多基因预后模型,Kaplan-Meier方法绘制生存曲线,ROC曲线评价预后模型的可靠性。结果:从481例DLBCL患者淋巴结样本及5例正常淋巴结样本中共提取DEARG 122个,其中上调基因4个,下调基因118个。GO富集主要集中在线粒体自噬、自噬调节、细胞对外部刺激的反应等本体学注释。KEGG富集主要集中在细胞衰老、NOD样受体信号通路、PI3K-Akt信号通路、PD-1/PD-L1信号通路等。对230个临床信息完整的样本进行生存分析,单因素Cox分析发现20个ARG与DLBCL患者整体生存明显相关,多因素Cox回归筛选出9个预后相关ARG(HIF1A、CAPN1、ITPR1、PRKCQ、TRAIL、HDAC1、TSC2、NRG3和MAPK3)建立DLBCL ARG预后模型。Kaplan-Meier生存曲线分析显示,高、低风险组患者的生存率比较具有显著差异(P<0.001)。多因素Cox回归分析结果表明,国际预后指数和风险值是DLBCL患者的独立预后指标(P<0.05),ROC曲线下面积分别为0.762和0.747。结论:DLBCL ARG预后模型可用于预测患者的预后,但仍需大样本的临床研究加以证实。

Objective:To screen the differential expression of diffuse large B-cell lymphoma(DLBCL)autophagyrelated gene(ARG),explore the mechanism of differential expression of autophagy gene(DEARG)in the occurrence and development of DLBCL and establish a prognostic model.Methods:Using the NCICCR database containing clinical information and gene expression profile data of 481 patients with DLBCL and the HADb database containing 232 ARGs,the differential expression of ARG in DLBCL was determined by R language,the relationship between ARG and the occurrence and development of DLBCL was analyzed by GO and KEGG,the polygene prognostic model was established by Cox regression algorithm,the survival curve was drawn by Kaplan-Meier method,and the reliability of the prognostic model was evaluated by ROC curve.Results:A total of 122 DEARGs were extracted from lymph node samples of 481 patients with DLBCL and 5 normal lymph nodes,including 4 up-regulated genes and 118 down-regulated genes.GO enrichment mainly focused on ontological annotations such as mitochondrial autophagy,autophagy regulation,and cell response to external stimuli.KEGG enrichment was mainly concentrated in cell senescence,NOD-like receptor signal pathway,PI3K-Akt signal pathway,and PD-1/PD-L1 signal pathway.Survival analysis was performed on 230 samples with complete clinical information.Univariate Cox analysis showed that 20 ARGs were significantly correlated with overall survival of DLBCL patients.Nine prognostic ARGs(HIF1A,CAPN1,ITPR1,PRKCQ,TRAIL,HDAC1,TSC2,NRG3,and MAPK3)were screened by multivariate Cox regression to establish DLBCL ARG prognostic model.Kaplan-Meier survival curve analysis showed that there was significant difference in survival rate between high risk group and low risk group(P<0.001).Multivariate Cox regression analysis showed that international prognostic index and risk value were independent prognostic indicators of DLBCL patients(P<0.05),the area under ROC curve was 0.762 and 0.747,respectively.Conclusion:DLBCL ARG prognostic model can be used to predict the prognosis of patients,but it still needs to be confirmed by a large sample of clinical studies.