基于内质网应激相关基因的鼻咽癌预后模型的构建与验证

Construction and Validation of A Prognostic Model for Nasopharyngeal Carcinoma Based on Endoplasmic Reticulum Stress-Related Genes

[目的]探究内质网应激(endoplasmic reticulum stress,ERS)相关基因对鼻咽癌(nasopharynx cancer,NPC)患者生存预测价值,构建基于ERS相关基因的NPC预后模型。[方法]从MsigDB和Genecards数据库中筛选ERS相关基因,并纳入到单因素Cox回归和LASSO回归,构建基于相关基因的NPC预后相关的风险评分模型,并用外部数据集进行验证。此外,纳入临床数据和风险评分构建列线图模型,探索风险评分与免疫治疗反应之间的关系。最后,通过qRT-PCR探索NPC特征基因的表达情况和功能。[结果]经分析获得1631个ERS相关基因,其中167个ERS相关基因在鼻咽组织中差异表达,上调26个,下调141个。筛选出5个具有统计学差异的基因,其中SPAG8、P4HTM、MLF1、GOLGA2在NPC组织内表达水平低于正常鼻咽组织,而GADD45A在NPC组织内表达水平高于正常鼻咽组织。基于这5个ERS相关基因构建风险评分模型。风险评分=(1.597×GADD45A+1.202×SPAG8+1.309×P4HTM+1.47×MLF1-1.586×GOLGA2)。风险评分模型预测1~3年生存率受试者工作特征曲线,曲线下面积分别为0.7569,0.8093和0.7187。高风险组B记忆细胞显著性低于低风险组(P<0.001),而树突状细胞浸润比例显著性高于低风险组(P<0.05)。qRT-PCR验证4种ERS相关基因(SPAG8、P4HTM、MLF1、GOLGA2)在NPC组织中的表达水平均低于癌旁组织(P<0.05),1种ERS相关基因(GADD45A)在NPC组织中的表达水平高于癌旁组织(P<0.01)。[结论]基于GEO数据库构建5个ERS相关基因组成的风险评分模型,列线图模型均能较准确地预测NPC患者预后,对NPC预后评估以及高风险群体筛查具有一定的参考价值,对NPC患者免疫治疗有一定的指导价值。

[Purpose]To construct and validate a prognostic model for nasopharynx cancer(NPC)based on the expression of endoplasmic reticulum stress(ERS)-related genes.[Methods]The expression of ERS-related genes in NPC were screened from MsigDB and Genecards databases.Univariate Cox regression and LASSO regression were used to construct a NPC prognosis-related risk score model based on these genes.The model was validated with external datasets.In addition,clinical data and risk scores were applied to construct nomogram model to explore the relationship between risk scores and immunotherapy response.Finally,the expression and function of NPC characteristic genes were explored by qRT-PCR.[Results]A total of 1631 ERS-related genes were obtained,among which 167 ERS-related genes were differentially expressed in nasopharyngeal tissues,with 26 up-regulated and 141 down-regulated.Five genes with statistical differences were screened out.Among them,the expression level of SPAG8,P4HTM,MLF1 and GOLGA2 in NPC tissues was lower than that in normal nasopharynx tissues,while the expression level of GADD45A in NPC tissues was higher than that in normal nasopharynx tissues.A risk score model was constructed based on these 5 ERS related genes.Risk score=(1.597×GADD45A+1.202×SPAG8+1.309×P4HTM+1.47×MLF1-1.586×GOLGA2).The area under receiver operating characteristic curve(AUC)of the risk score model for predicting 1-,2-,3-year survival of NPC patients was 0.7569,0.8093,and 0.7187,respectively.B memory cells in high-risk group was significantly lower than that in low-risk group(P<0.001),and the proportion of dendritic cells activated in cell infiltration was significantly higher than that in low-risk group(P<0.05).According to the results of qRT-PCR,the expression level of ERS-related genes SPAG8,P4HTM,MLF1 and GOLGA2 in NPC tissues was lower than that in pericancerous tissues(P<0.05),and the expression level of ERS-related gene GADD45A in NPC tissues was higher than that in pericancerous tissues(P<0.01).[Conclusion]The risk score model of 5 ERS-related genes based on GEO database and nomogram models could predict the prognosis of NPC patients accurately.It has certain reference value for NPC prognosis assessment and screening of high-risk groups,and has certain guiding value for immunotherapy of NPC patients.