背景：本研究通过内质网应激相关基因构建膀胱癌（BLCA）的分子亚型和预后模型，从而有助于临床指导准确的治疗和预后评估。方法：从The Cancer Genome Atlas（TCGA）和Gene Expression Omnibus（GEO）数据库下载膀胱癌（BLCA）基因表达数据。通过GeneCards数据库获得内质网应激相关基因进行聚类分析，结果建立了新的膀胱癌分子分型。此外，我们还探讨了每一种分型在免疫微环境、突变和药物筛选方面的特征。通过对内质网应激相关基因进行单变量Cox、LASSO和多变量Cox分析，我们还开发了四个基因签名，并验证了模型在GSE32894和GSE13507队列中的预后效果。最后，我们评估了高低内质网应激得分组的临床数据的预后价值，并通过Nomogram构建预后得分线图。结果：我们构建了四种膀胱癌分子亚型（C1-C4），其中C2患者预后不良，C3患者预后较好。C2具有较高的TP53突变、显著的免疫细胞浸润和高免疫评分。相反，C3具有较高的FGFR3突变、不显著的免疫细胞浸润和减少的免疫检查点表达。之后，我们建立了内质网应激相关的风险签名来计算ERS得分，包括ATP2A3、STIM2、VWF和P4HB。在GSE32894和GSE13507中，该签名还具有良好的预测价值。此外，ERS得分也与各种临床特征有很好的相关性。最后，我们将ERS分群和ERS得分进行了相关性比较。ERS得分高的患者更可能具有C2表型，而ERS得分低的患者则是C3。结论：总之，我们通过内质网应激相关基因鉴定了四种新的BLCA分子亚型，这可以为个体化治疗提供新的思路。由内质网应激相关基因构建的预后模型可用于预测临床结果。本研究对于BLCA个体化治疗和机制研究做出了贡献。版权所有©2023 Lin、Li、Li、Shen、Wu、Zhang、Li、Yang、Wang、Li、Fu、Guo和Hu。

Background: This study constructs a molecular subtype and prognostic model of bladder cancer (BLCA) through endoplasmic reticulum stress (ERS) related genes, thus helping to clinically guide accurate treatment and prognostic assessment. Methods: The Bladder Cancer (BLCA) gene expression data was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We clustered by ERS-related genes which obtained through GeneCards database, results in the establishment of a new molecular typing of bladder cancer. Further, we explored the characteristics of each typology in terms of immune microenvironment, mutations, and drug screening. By analyzing the ERS-related genes with univariate Cox, LASSO and multivariate Cox analyses, we also developed the four-gene signature, while validating the prognostic effect of the model in GSE32894 and GSE13507 cohorts. Finally, we evaluated the prognostic value of the clinical data in the high and low ERS score groups and constructed a prognostic score line graph by Nomogram. Results: We constructed four molecular subtypes (C1- C4) of bladder cancer, in which patients with C2 had a poor prognosis and those with C3 had a better prognosis. The C2 had a high degree of TP53 mutation, significant immune cell infiltration and high immune score. In contrast, C3 had a high degree of FGFR3 mutation, insignificant immune cell infiltration, and reduced immune checkpoint expression. After that, we built ERS-related risk signature to calculate ERS score, including ATP2A3, STIM2, VWF and P4HB. In the GSE32894 and GSE13507, the signature also had good predictive value for prognosis. In addition, ERS scores were shown to correlate well with various clinical features. Finally, we correlated the ERS clusters and ERS score. Patients with high ERS score were more likely to have the C2 phenotype, while patients with low ERS score were C3. Conclusion: In summary, we identified four novel molecular subtypes of BLCA by ERS-related genes which could provide some new insights into precision medicine. Prognostic models constructed from ERS-related genes can be used to predict clinical outcomes. Our study contributes to the study of personalized treatment and mechanisms of BLCA.Copyright © 2023 Lin, Li, Li, Shen, Wu, Zhang, Li, Yang, Wang, Li, Fu, Guo and Hu.