m6A修饰相关的长链非编码RNA对肾透明细胞癌预后和免疫治疗的研究

Analysis of m6A Modification-related Long Non-coding RNA on Prognosis and Immunotherapy of Clear Cell Renal Cell Carcinoma

目的探究与N6-甲基腺嘌呤(m6A)相关的长链非编码RNA(long non-coding RNA,lncRNA)对肾透明细胞癌(renal clear cell carcinoma,ccRCC)预后和免疫治疗的特征。方法通过TCGA数据库下载532例ccRCC患者组织和72例正常肾组织的转录组数据和临床特征数据,利用共表达和单因素COX回归分析筛选与预后和m6A相关的lncRNA。基于预后和m6A相关的lncRNA的表达进行聚类分析,分析两种聚类分型与免疫检查点程序性死亡配体1(programmed death-ligand 1,PD-L1)和细胞毒性T淋巴细胞相关抗原-4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)表达的相关性。构建LASSO COX回归风险预后模型,验证其临床应用价值,利用ESTIMATE方法比较ccRCC肿瘤微环境的差异,免疫表观评分(immunophenoscore,IPS)预测ccRCC对免疫检查点抑制剂(immune checkpoint inhibitor,ICI)的敏感度。结果通过共表达和单因素COX回归分析筛选出29个与预后和m6A相关的lncRNA,大多数在ccRCC组织中表达上调,而COL18A1-AS1、AC007066.2和AC018752.1则表达下调。通过聚类分析将532例ccRCC组织样本分为cluster1组和cluster2组,cluster2组预后更差,PD-L1和CTLA4表达更高。利用LASSO COX回归算法确定8个与预后和m6A相关的lncRNA,建立ccRCC风险预后模型,该模型在不同临床特征中均有较好的预测价值。依据模型计算风险值将患者分为高风险组和低风险组。高风险组患者预后更差,富含更多免疫细胞成分,对ICI治疗更敏感。结论m6A相关的lncRNA对ccRCC患者的预后预测和免疫治疗指导具有重要意义。

Objective To investigate the prognostic and immunotherapy characteristics of N6-methyladenine(m6A)-related long non-coding RNA(lncRNA)in renal clear cell carcinoma(ccRCC).Methods Transcriptome data and clinical characteristic data of 532 ccRCC tissues and 72 normal kidney tissues were downloaded from the TCGA database,and lncRNAs related to prognosis and m6A were screened by co-expression and univariate COX regression analysis.Cluster analysis was performed based on the prognosis and the expression of m6A-related lncRNA,the correlation between the two clusters and the expression of immune checkpoints programmed death-ligand 1(PD-L1)and cytotoxic T lymphocyte-associated antigen-4(CTLA-4)was analyzed.The LASSO COX regression risk prognosis model was constructed to verify its clinical application value,and the ESTIMATE method was used to compare the differences in the tumor microenvironment of ccRCC,and the immunophenoscore(IPS)predicted the sensitivity of ccRCC to immune checkpoint inhibitor(ICI).Results Twenty-nine lncRNAs associated with prognosis and m6A were screened by co-expression and univariate COX regression analysis,most of which were up-regulated in ccRCC tissues,while COL18A1-AS1,AC007066.2 and AC018752.1 were down-regulated.The 532 ccRCC tissue samples were divided into cluster1group and cluster2group by cluster analysis.The cluster2group had worse prognosis and higher expression of PD-L1 and CTLA4.Eight lncRNAs related to prognosis and m6A were identified by LASSO COX regression algorithm to establish a ccRCC risk prognostic model,which has good predictive value in different clinical features.Patients were divided into high-risk group and low-risk group based on risk scores calculated by the risk prognostic model.Patients in the high-risk group had a worse prognosis,more immune cell components,and were more sensitive to ICI treatment.Conclusion m6A-related lncRNA is of great significance for the prognosis prediction and immunotherapy guidance in ccRCC patients.