基于铜死亡相关基因构建结肠腺癌临床预后模型并验证

Establishment and verification of a novel Cuproptosis-related genes signature in colonic adenocarcinoma

目的旨在构建结肠腺癌(colonic adenocarcinoma,COAD)中铜死亡相关基因(Cuproptosis-related genes,CRGs)的预后模型,探讨CRGs在COAD中的表达与预后的关系。方法从TCGA数据库下载了正常和COAD患者的转录组和临床数据,并从GEO数据库下载数据集GSE39582作为外部验证集。基于铜死亡相关基因表达量,对TCGA数据进行共识聚类以确定新的肿瘤亚型。采用单因素Cox回归分析、LASSO回归分析筛选预后基因并构建预后风险模型。并通过Kaplan-Meier生存分析、受试者工作特征(receiver operating characteristic,ROC)曲线下的面积(area under the curve,AUC)和一致性指数(concordance index,C-index)对模型进行评价。用GSE44001数据集对模型进行外部验证。基于风险评分及临床因素构建列线图,预测患者的生存率。并进行免疫浸润、GSEA分析、免疫检查点、药敏分析、肿瘤微环境和干细胞指数的研究,系统地阐述COAD中CRGs和免疫的相关性。结果21个CRGs在COAD组织及正常组织中差异表达。单变量Cox回归及Lasso回归分析确定了五个预后相关基因(SDHB,CCS,DLAT,FDX1,CP)并构建模型。Kaplan-Meier分析表明,高风险患者OS显著低于低风险患者(P<0.01),并在GEO队列中取得了验证(P<0.05)。风险模型的AUC值为0.734,表明预后值有统计学意义,模型具有一定的准确性。一致性分析和ROC结果表明,列线图模型有较好的预后预测准确性。这5个CRGs主要参与线粒体、免疫应答和代谢途径,是COAD预后的独立因素,并与免疫细胞浸润、免疫检查点以及肿瘤微环境和干细胞指数密切相关。结论构建了5个铜死亡相关基因的结肠腺癌预后模型,有可能作为未来临床实践中有效的预后标志物。

Objective This study aims to construct a prognosis risk model,investigating the relationship between the expression of Cuproptosis-related genes(CRGs)and the prognosis in colonic adenocarcinoma(COAD).Methods The transcriptome and clinical data of normal and COAD patients were downloaded from TCGA database,and the dataset GSE39582 from GEO database was downloaded as an external validation set.Based on the expression of CRGs,the data of TCGA were consensus clustered to identify novel tumor subtypes.Univariate Cox regression analysis and LASSO regression analysis were used to explore cuproptosis-related genes associated with prognosis,and constructed a prognosis risk model.The model was evaluated through the Kaplan-Meier survival analysis,the receiver operating characteristic area under the curve(AUC)and concordance index(C-index).Based on the risk score and clinical factors,a nomogram was constructed to predict the survival of patients.Performed immune infiltration,GSEA analysis,immune checkpoint,drug sensitivity analysis,tumor microenvironment and stem cell index,systematically elaborated the prognostic and immune correlation of CRGs in COAD.Results Totally,the results showed that 21 CRGs expressed differentially in COAD.Univariate Cox regression analysis and LASSO regression analysis identified five risk-related genes(SDHB,CCS,DLAT,FDX1 and CP)related to patients’OS.Kaplan-Meier analysis shows that patients at high risk have lower survivability(P<0.01),which was verified in the GEO queue(P<0.05).And the calculated value of the ROC curve is 0.734,indicating that the prognostic value was statistically significant.The results of consistency analysis and ROC showed that the nomogram model has effective prognostic accuracy.These 5 independent factors of COAD prognosis CRGs were mainly involved in the mitochondrion,immune response and metabolic pathways and may be closely associated with immune-cell infiltration,immune checkpoints,tumor microenvironment and stem cell index.Conclusion A colonic adenocarcinoma prognosis model of five CRGs is established,which may be used as an effective prognostic marker in clinical practice in the future.