膀胱尿路上皮癌蛋白组学相关个体化预后特征的推导与验证

Derivation and validation of proteomic related individualized prognostic signatures of bladder urothelial carcinoma

目的筛选出膀胱尿路上皮癌(urothelial carcinoma,UC)的蛋白组学相关预后特征(proteomics-related prognostic signatures,PRPS),从而预测UC患者的生存预后。方法通过Cox回归模型确定UC中的PRPS,以多因素Cox回归的结果计算每一位患者的风险评分(risk score,RS)。以RS中位值为标准进行风险分组并构建RS预后模型,依次进行总生存时间(overall survival,OS)、无进展生存时间(progression free survival,PFS)分析,绘制包括风险分组的临床列线图来预测患者的预后,并通过受试者工作特征(receive operating characteristic,ROC)曲线与决策曲线分析(decision curve analysis,DCA)进行验证;然后进行基因组学分析,与蛋白组学研究互为补充。采用基因富集分析与免疫细胞浸润分析探究在风险分组中活跃的生物学功能、作用通路及肿瘤微环境(tumor microenvironment,TME)变化。结果在UC中确定6个PRPS作为预后指标。生存分析(Kaplan-Meier,KM)表明,高风险组患者的OS与FPS明显低于低风险组,差异有统计学意义(P<0.001)。ROC曲线表明,RS预后模型有可靠的预测能力,1年、2年、3年生存率的ROC曲线下面积(area under curve,AUC)分别为0.710、0.709、0.719。列线图用来协助临床医生预测UC患者的生存率是可靠的。基因组学分析表明,基因与蛋白质存在着时间上的差异性。基因富集分析表明,PRPS的生物学功能与通路富集在人类免疫应答上。免疫细胞浸润性分析发现,中性粒细胞及NK细胞在高风险人群中显著高表达,差异有统计学意义(P<0.05)。结论PRPS可作为新的肿瘤标志物来预测UC患者的生存率及肿瘤的恶性程度。

Objective:To screen the proteomics-related prognostic signatures(PRPS)of urothelial carcinoma(UC)from the public database to predict the survival prognosis of patients.Methods:The PRPS in UC was determined by Cox regression model,and the risk score(RS)of each patient was calculated by the results of multivariate Cox regression.The risk was grouped according to the RS median value and the risk prognosis model was constructed.The overall survival(OS)and progression free survival(PFS)between groups were analyzed in turn,and the clinical nomogram including risk grouping was drawn to predict the prognosis of patients.Gene enrichment analysis and immune cell infiltration analysis were used to explore the active biological functions,action pathways and changes in tumor microenvironment(TME)in risk groups.Results:Finally,6 PRPS were identified as independent prognostic proteins in UC.Kaplan Meier(KM)analysis showed that OS and FPS in high-risk group were significantly shorter than those in low-risk group(P<0.001).ROC curve showed that our model had reliable prediction ability(AUC of 1-year,2-year and 3-year survival rates are 0.710,0.709 and 0.719 respectively).The clinical nomogram showed a strong efficacy in predicting the survival rate of UC patients.Genomic analysis showed that there were temporal differences between genes and proteins.Gene enrichment analysis showed that the biological functions and pathways of PRPS were enriched in human immune response.Immunocyte infiltration analysis showed that neutrophils and NK cells were highly expressed in high-risk population.Conclusion:The PRPS can be a new tumor marker for UC patients in predicting the survival rate of UC patients and the malignant degree of tumors.