子宫内膜癌铜死亡相关基因和PD-1预后模型构建及免疫浸润分析

Construction of cuproptosis-related genes and PD-1 prognostic signature for uterine corpus endometrial carcinoma and analysis of immune infiltration

目的寻找子宫内膜癌(UCEC)预后标志物与程序性死亡受体1(PD-1)免疫基因的相关性,为改善患者生存预后提供帮助。方法通过TCGA数据库分析545例子宫内膜癌样本和177例正常样本中铜死亡相关基因的差异表达以及临床病理特征,进行生存分析及基因表达差异分析,选取其中与PD-1相关的高表达的基因进行基因相关性分析和免疫浸润分析,并构建其预后风险模型。结果铜死亡基因当中,有4个基因(ATP7B、SLC31A1、CDKN2A、PDHA1)在子宫内膜癌中上调,有4个基因(GLS、MTF1、LIPT1、LIAS)在子宫内膜癌中下调(P<0.01)。PD-1与3个铜死亡基因(ATP7B、CDKN2A、PDHB)的表达水平呈显著相关性(P<0.01),与DLAT、DLD、FDX1、MTF1、PDHA1的表达水平有相关性(P<0.05),与其他铜死亡基因无相关。铜死亡相关基因CDKN2A在子宫内膜癌中呈显著高表达。CDKN2A的表达水平在晚期癌症组中明显高于早期癌症组。采用log-rank检验方法比较CDKN2A高表达组和CDKN2A低表达组的预后差异,CDKN2A高表达组的总生存期比CDKN2A低表达组差,受试者工作特征曲线(ROC曲线)表明CDKN2A表达预测1、3、5年生存率的曲线下面积(AUC)分别为0.614、0.670、0.682。采用Cox分析法探讨子宫内膜癌患者的CDKN2A表达与总生存期的关系,单因素分析显示年龄(HR=1.03446,P=0.00061)、pTNM分期(HR=1.998,P<0.0001)、肿瘤分级(HR=1.87393,P=0.00016)和CDKN2A表达(HR=1.26224,P<0.0001)与总生存期显著相关。多因素分析显示CDKN2A表达是子宫内膜癌患者预后的独立因素(P=0.04214<0.05)。结论铜死亡相关基因CDKN2A在子宫内膜癌中高表达并影响患者预后,CDKN2A在子宫内膜癌中与免疫检查点基因PD-1的表达密切相关,CDKN2A有望成为癌症免疫治疗的潜在靶点。

Objective With a view to find the correlation between prognostic markers of uterine corpus endometrial carcinoma(UCEC)and programmed death 1(PD-1)immune gene,we provide to help for improving the survival and prognosis of patients.Methods The differential expression and clinicopathological characteristics of cuproptosis-related genes in 545 uterine corpus endometrial carcinoma samples and 177 normal samples were analyzed by TCGA database.Survival analysis and gene expression difference analysis were carried out.The genes with high expression related to PD-1 were selected for gene correlation analysis and immune infiltration analysis,and its prognostic risk signature was constructed.Results Among the cuproptosisrelated genes,4 genes(ATP7B,SLC31A1,CDKN2A,PDHA1)were up-regulated in uterine corpus endometrial carcinoma,and 4 genes(GLS,MTF1,LIPT1,LIAS)were down-regulated in uterine corpus endometrial carcinoma(P<0.01).PD-1 was significantly correlated with the expression levels of three cuproptosis-related genes(ATP7B,CDKN2A,PDHB)(P<0.01),and was correlated with the expression levels of DLAT,DLD,FDX1,MTF1,PDHA1(P<0.05),but was not correlated with other cuproptosis-related genes.Cuproptosis-related gene CDKN2A was significantly overexpressed in uterine corpus endometrial carcinoma.The expression level of CDKN2A was significantly higher in the advanced cancer group than in the early cancer group.log-rank test was used to compare the prognostic difference between the CDKN2A high expression group and the CDKN2A low expression group.The overall survival of the CDKN2A high expression group was worse than that of the CDKN2A low expression group.Receiver operating characteristic curve(ROC curve)showed that the area under the curve(AUC)for CDKN2A expression predicting 1-,3-,and 5-year survival were 0.614,0.670,and 0.682,respectively.Cox analysis was used to investigate the relationship between CDKN2A expression and overall survival in patients with uterine corpus endometrial carcinoma.Univariate analysis showed age(HR=1.03446,P=0.00061),pTNM stage(HR=1.998,P<0.0001),tumor grade(HR=1.87393,P=0.00016)and CDKN2A expression(HR=1.26224,P<0.0001)were significantly associated with overall survival.Multivariate analysis showed that CDKN2A expression was an independent prognostic factor in patients with uterine corpus endometrial carcinoma(P=0.04214<0.05).Conclusion Cuproptosis-related gene CDKN2A is highly expressed in uterine corpus endometrial carcinoma and affects the prognosis of patients.CDKN2A is closely related to the expression of immune checkpoint gene PD-1 in uterine corpus endometrial carcinoma.CDKN2A is expected to become a potential target for cancer immunotherapy.