基于细胞衰老基因的膀胱癌预后及免疫治疗风险模型的构建和验证

张鹏; 杨倩; 易东风

doi:10.3971/j.issn.1000-8578.2023.22.1214

基于细胞衰老基因的膀胱癌预后及免疫治疗风险模型的构建和验证

Construction and Validation of A Risk Model for Predicting Prognosis and Immunotherapy Response of Bladder Cancer Based on Cellular Senescence-related Genes

摘要

摘要:
目的通过构建细胞衰老相关标志(SRS)风险评分模型评估膀胱癌的预后和对免疫治疗的反应，探讨SRS在膀胱癌中的临床应用价值。
方法从TCGA-BLCA筛选出细胞衰老基因，根据LASSO回归筛选出其中的细胞衰老相关标志基因。基于衰老标志基因构建膀胱癌风险评分模型分析TCGA-BLCA高、低风险组的生存差异和模型拟合度，单因素、多因素Cox回归分析膀胱癌预后危险因素。分析GEO-BLCA、IMvigor210数据库中高、低风险组的总体生存差异和免疫治疗反应。根据膀胱癌组织和正常癌旁组织中β-gal显色反应，明确膀胱癌组织中是否存在细胞衰老。
结果共筛选出8个细胞衰老标志基因，根据标志基因构建的风险评分中位数将患者分为高、低风险组。高风险组患者的5年生存率低于低风险组患者(训练集及验证集P < 0.05)，TCGA-BLCA和GSE13507患者1、3、5年OS的ROC曲线下面积分别为0.657、0.660、0.688和0.665、0.665、0.613。SRS风险评分可作为膀胱癌患者预后的独立危险因素，膀胱癌免疫治疗中反应组较非反应组的SRS风险评分更低(P < 0.05)。膀胱癌组织β-gal染色阳性，癌旁正常组织β-gal染色阴性。
结论膀胱癌组织中存在细胞衰老现象，SRS风险评分可以预测膀胱癌患者的临床预后，评分较低的患者可以从免疫治疗中获益。SRS是膀胱癌预后和免疫治疗反应的一个可靠的生物标志物。

Abstract:
Objective To evaluate the prognosis and immunotherapy response of patients with bladder cancer by constructing a risk-score model of cellular senescence-related signature (SRS), as well as to explore the clinical application value of SRS in bladder cancer.
Methods Senescence genes were screened from TCGA-BLCA, and cellular SRS genes were screened according to LASSO regression. A bladder cancer risk-score model was constructed based on the SRS genes to analyze the survival difference and model-fit degree of TCGA-BLCA high- and low-risk groups. Univariable and multivariable Cox regression was used to analyze the prognostic risk factors of bladder cancer. Overall survival differences of high- and low-risk groups in GEO-BLCA database were verified, and variations in immunotherapy responses were analyzed in IMvigor210 databases. According to the result of β-gal chromogenic reaction in bladder cancer and normal paracancer tissues, the existence of cell senescence was determined.
Results Eight marker genes were screened, and patients were divided into high- and low-risk groups according to the median risk score constructed by the marker genes. The 5-year survival rate of high risk group was lower than that of low risk group (training and validation sets P < 0.05). The area under the ROC curve of TCGA-BLCA in 1-, 3-, and 5-year were 0.657, 0.660, and 0.688, and those for GSE13507 were 0.665, 0.665, and 0.613, respectively. SRS risk score can be used as an independent risk factor for the prognosis of patients with bladder cancer. The SRS risk score in the response group was lower than that in the non-response group during bladder cancer immunotherapy (P < 0.05). The β-gal staining of bladder cancer tissue was positive, but the β-gal staining of adjacent normal tissue was negative.
Conclusion Cell senescence occurs in bladder cancer tissues. SRS risk score can predict the clinical prognosis of patients with bladder cancer, and patients with low score can benefit from immunotherapy. SRS is a reliable biomarker for the prognosis and immunotherapy response of bladder cancer.

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