摘要
目的 基于内质网应激(ERS)相关长链非编码核糖核苷酸(lncRNA)构建肾透明细胞癌(ccRCC)患者预后模型,探讨免疫细胞浸润与ccRCC患者预后的相关性,并寻找可用于治疗ccRCC的新药物.方法 从癌症基因组图谱(TCGA)数据库获取ccRCC肿瘤与癌旁组织的转录组和临床数据.从MSigDB数据库获取ERS相关基因集.通过Pearson相关性分析筛选ERS共表达lncRNA.通过Lasso回归和单、多因素Cox回归分析筛选有预后意义的ERS相关lncRNA(ERSRL)并构建预后模型.根据预后模型公式计算每个样品的风险值,以中位值为界,将患者分成高、低风险组进行生存差异分析.通过生存曲线、受试者特征曲线、校准曲线评估该预后模型的预测效能.利用CIBERSORT数据库探讨高、低风险组的免疫细胞浸润情况.利用GDSC数据库探讨ERSRL和药物敏感性之间的关系,并筛选对ccRCC具有潜在疗效的药物.结果 筛选得到9个有独立预后价值的lncRNA构建预后模型.Kaplan-Meier分析表明高、低风险组之间存在明显生存差异.单、多因素Cox回归分析表明年龄、分级、分期和风险评分可作为ccRCC的独立预后影响因素.训练集风险评分模型1、3、5年生存率的曲线下面积(AUC)分别为0.754(95％CI:0.659～0.848)、0.744(95％CI:0.667～0.815)、0.759(95％CI:0.662～0.820),C-index 为 0.777(95％CI:0.759～0.796).免疫浸润结果表明,与低风险组相比,在高风险组中的浆细胞、激活的记忆CD4+T细胞、调节性T细胞、M0巨噬细胞、活化肥大细胞浸润水平高.药物敏感性分析筛选得到AZD8055等12种对ccRCC具有潜在疗效的药物.结论 基于9个ERSRL构建的ccRCC患者的生存预后预测模型预测效能较好.AZD8055等12种药物对ccRCC具有潜在疗效.
Abstract
Objective To construct a prognostic model of clear cell renal cell carcinoma(ccRCC)based on endoplasmic reticulum stress(ERS)-related long non-coding ribonucleotides(lncRNA),so as to explore the correlation between immune cell infiltration and prognosis of ccRCC patients,and to search for new drugs for the treatment of ccRCC.Methods The transcriptome and clinical data of cancerous and paracancerous tissues of ccRCC were obtained from the TCGA database.The ERS-associated gene set was obtained from the MSigDB database.ERS co-expressed lncRNAs were screened with Pearson correlation analysis.ERS-related lncRNA(ERSRL)with prognostic significance were screened with Lasso regression,univariate and multivariate Cox regression analyses,and a prognostic model was constructed.The risk value of each sample was calculated according to the prognostic model formula.The patients were divided into high-risk and low-risk groups for survival difference analysis.The predictive performance of the prognostic model was evaluated with survival curve,receiver operating characteristic(ROC)curve and calibration curve.The infiltration of immune cells in high-and low-risk groups was analyzed with CIBERSORT database.The relationship between ERSRL and drug sensitivity was analyzed with GDSC database to identify drugs with potential efficacy against ccRCC.Results A total of 9 lncRNAs with independent prognostic significance were screened to construct the prognostic model.Kaplan-Meier analysis showed significant survival differences between the high-and low-risk groups.Univariate and multivariate Cox regression analyses showed that age,grade,stage and risk score could be used as independent prognostic factors.The area under the ROC curve(AUC)of the 1-,3-,and 5-year survival rates of the training set were 0.754(95％CI:0.659-0.848),0.744(95％CI:0.667-0.815),and 0.759(95％CI:0.662-0.820),respectively,and the C-index was 0.777(95％CI:0.759-0.796).Immune infiltration results showed that plasma cells,activated memory CD4+T cells,regulatory T cells,M0 macrophages,and activated mast cell infiltration levels were higher in the high-risk group than those in the low-risk group.Drug susceptibility analysis identified 12 drugs with potential curative effects on ccRCC,including AZD8055.Conclusion Based on 9 ERSRLs,a prognostic model for ccRCC patients was constructed,and 12 drugs with potential therapeutic effects were screened,including AZD8055.
基金项目
山西省重点研发计划项目(202102130501003)
山西省重点研发计划项目(201903D311011)
山西省回国留学人员科研资助项目(HGKY2019057)
山西省研究生教育创新项目(2022Y426)
维普
万方数据