构建结肠癌预后的免疫相关基因风险标志物及其对结肠癌患者预后的预测

Construction of immune related gene risk markers for prognosis of colon cancer and its prediction of prognosis in colon cancer patients

目的开发基于免疫相关基因(immune-related genes,IRGs)的预后风险的预测标志物并评估其在结肠癌患者预后预测中的价值。方法从TCGA数据库中收集452例结肠癌患者的基因芯片数据集,从ImmPort数据库中获得2498个IRGs数据集,取交集后采用单因素和多因素Cox比例风险回归分析,筛选并构建IRGs基因模型。为评估基因模型预测预后的价值,采用Cox比例风险回归分析IRGs模型、临床病理特征与结肠癌患者预后的相关性,并分析风险评分与免疫细胞浸润的关系。结果在结肠癌组织中共确定了206个差异表达的IRGs,经过单因素和多因素Cox比例风险回归分析,确定了11个IRGs标志物,即溶质载体家族10成员2(SLC10A2)、C-X-C基序趋化因子配体5(CXCL5)、C-C基序趋化因子配体(CCL28)、免疫球蛋白kappa变量1D-42(IGKV1D-42)、嗜铬粒蛋白A(CHGA)、内皮细胞特异性分子1(ESM1)、胃泌激素释放肽(GRP)、斯钙素2抗体(STC2)、尿皮质素(UCN)、催产素受体(OXTR)和免疫球蛋白重常数γ1(IGHG1)。根据IRGs风险标志物的风险值的中位数将结肠癌患者分为高风险组和低风险组,高风险组患者的总生存时间(OS)差于低风险组患者(P<0.001)。时间依赖的ROC曲线下面积(AUC)为0.754,提示IRGs模型对结肠癌患者预后有较好的预测能力。IRGs风险评分高,则结肠癌T分期晚(T3~T4),淋巴结转移多(N1~N2)及临床分期晚(Ⅲ~Ⅳ),P<0.05。除中性粒细胞外,B细胞、CD4^(+)T细胞、CD8^(+)T细胞、树突状细胞和巨噬细胞浸润密度随风险值评分增高而增高(P<0.05)。结论本研究筛选的11个IRGs基因模型,其风险值可用于预测结肠癌患者的预后,并可作为评估结肠癌预后的生物标志物。

Objective To develop an immune-related genes(IRGs)based prognostic signature and evaluate the value in predicting prognosis in patients with colon cancer.Methods Gene chip data sets of 452 colon cancer patients were collected from the TCGA database,and 2498 IRGs data sets were obtained from the ImmPort database.After taking the intersection,univariate and multivariate Cox proportional hazards regression analysis were used to screen and construct the IRGs gene model.To evaluate the prognostic value of genetic models,Cox proportional hazards regression was used to analyze the correlation between IRGs model/clinicopathological features with prognosis of colon cancer.The relationship between risk score and immune cell infiltration was analyzed too.Results A total of 206 differentially expressed IRGs were identified in colon cancer tissues,and 11 kinds of IRGs were identified by univariate and multivariate Cox proportional hazards regression analysis:solute carrier family 10 member 2(SLC10A2),C-X-C motif chemokine ligand 5(CXCL5),C-C motif chemokine ligand 28(CCL28),immunoglobulin kappa variable 1D-42(IGKV1D-42),chromogranin A(CHGA),endothelial cell specific molecule 1(ESM1),gastrin releasing peptide(GRP),stanniocalcin 2(STC2),urocortin(UCN),oxytocin receptor(OXTR)and immunoglobulin heavy constant gamma 1(IGHG1).Colon cancer patients were divided into high risk group and low risk group according to the median value of risk value of IRGs risk markers.Patients in the high risk group had shorter overall survival(OS)than that in the low risk group(P<0.001).The area of the time-dependent ROC curve(AUC)was 0.754,suggesting that IRGs model had a good ability to predict the prognosis of colon cancer patients.The higher the risk value of IRGs,the later T stage of colon cancer(T3–T4),the more lymph node metastasis(N1–N2)and the later clinical stage of colon cancer(Ⅲ–Ⅳ),P<0.05.Except for neutrophils,the infiltration density of B cells,CD4^(+)T cells,CD8^(+)T cells,dendritic cells and macrophages were significantly increased with the increased of the risk value(P<0.05).Conclusion The risk values of the 11 kinds of IRGs gene models screened in this study can be used to predict the prognosis of colon cancer patients,and can be used as biomarkers to evaluate the prognosis of colon cancer patients.