基于铜死亡相关LncRNAs评估胃癌预后、免疫浸润及中药预测

Assessment of gastric cancer prognosis,immune infiltration based on cuproptosis⁃related LncRNAs and prediction of traditional Chinese medicine

目的:基于铜死亡相关的LncRNAs(cuproptosis-related LncRNAs,CRLs)建立胃癌(gastric cancer,GC)预后模型,预测调控铜死亡相关基因(cuproptosis-related genes,CRGs)的中药。方法:从癌症基因组图谱(the cancer genome atlas,TCGA)数据库获取443例GC的临床资料及RNA-seq,通过Pearson分析、Cox回归、最小绝对收缩和选择算子(least absolute shrinkage and selection operator,LASSO)回归等方法筛选CRLs构建预测GC预后的风险模型,结合风险评分和临床特征构建列线图。通过受试者工作特征曲线、Kaplan-Meier曲线和C-指数验证模型的准确性。评估风险评分与免疫浸润、免疫检查点基因表达和化疗/靶向药的相关性。应用Coremine Medical数据库预测调控CRGs的潜在中药。结果:基于7个CRLs(AP001107.9、VCAN-AS1、AC016394.2、LINC02675、AC100814.1、HAGLR和LINC01094)的风险评分构建GC风险模型。风险模型预测GC患者1、3、5年生存率的AUC分别为0.720、0.682、0.711,其预后价值优于年龄、Grade分级、TNM分期。结合年龄、TNM分期的风险模型预测GC患者1年生存率的AUC为0.793。风险评分与肿瘤浸润淋巴细胞、调节性T细胞等免疫细胞富集程度及LAG3、ICOS、CD28、NRP1等22个免疫检查点基因表达和13种化疗/靶向药的敏感性具有相关性。对CRGs具有潜在调节作用的中药有58种,其功效以清热解毒、活血止痛为主,主归肝、脾、肺经,螺旋藻和蛇床子对铜死亡机制的关键基因FDX1具有潜在调控作用。结论:基于7个CRLs构建的风险模型可评估GC的预后、免疫,螺旋藻及蛇床子可能对铜死亡机制具有重要的调控效能。

Objective:Constructing a prognostic model for gastric cancer(GC)based on cuproptosis⁃related LncRNAs(CRLs)and predict the traditional Chinese medicine that regulates cuproptosis⁃related genes(CRGs).Methods:Clinical data and RNA⁃seq of 443 GC cases were obtained from The Cancer Genome Atlas database,and CRLs were screened by Pearson analy⁃sis,Cox regression,and least absolute shrinkage and selection operator regression to construct a risk model to predict GC progno⁃sis,and the nomogram was constructed by combining risk scores and clinical characteristics.The accuracy of the model was vali⁃dated by the receiver operating characteristic curve,Kaplan⁃Meier curves and C⁃index.The correlation of risk scores with immune infiltration,immune checkpoint gene expression and chemotherapy/targeted agents was assesssed.The Coremine Medical data⁃base was applied to predict potential traditional Chinese medicine that regulates CRGs.Results:Risk models for GC were con⁃structed based on the risk scores of seven CRLs(AP001107.9,VCAN⁃AS1,AC016394.2,LINC02675,AC100814.1,HA⁃GLR,and LINC01094).The AUC of the risk model predicting 1⁃,3⁃,and 5⁃year survival in GC patients was 0.720,0.682,and 0.711,respectively and its prognostic value was better than age,grade classification,and TNM stage.The AUC of the risk model combining age and TNM stage to predict 1⁃year survival in GC patients was 0.793.The risk score correlated with the degree of en⁃richment of immune cells such as tumor⁃infiltrating lymphocytes and regulatory T cells and the expression of 22 immune check⁃point genes such as LAG3,ICOS,CD28,NRP1 and the sensitivity of 13 chemotherapeutic/targeted agents.There were 58 tradi⁃tional Chinese medicine with potential regulatory effects on CRGs,mainly for clearing heat and detoxing,promoting blood circula⁃tion and relieving pain,which were mainly attributed to the liver,spleen and lung meridians.Spirulina and osthole had potential regulatory effects on FDX1,a key gene in the death mechanism of cuproptosis.Conclusion:A risk signature constructed based on seven CRLs could assess the prognosis and immunity of GC,and Spirulina and Serpentine may have important regulatory efficacy on the mechanism of copper cuproptosis.