Muscle-invasive bladder cancer (MIBC) is distinguished by its pronounced invasiveness and unfavorable prognosis. Immunotherapy and targeted therapy have emerged as key treatment options for various types of cancer. Altered metabolism is a defining characteristic of cancer cells, and there is mounting evidence suggesting the important role of glutamine metabolism (GM) in tumor metabolism. Nevertheless, the relationship between GM and clinical outcomes, immune microenvironment, and immunotherapy in MIBC remains unknown. This study employed Mendelian randomization to explore the causal relationship between blood metabolites and bladder tumors. We systematically evaluated 373 glutamine metabolism-related genes and identified prognostic-related genes, leading to the construction of a glutamine-associated prognostic model. Further analysis confirmed the correlation between high and low-risk groups with the tumor microenvironment, immune cell infiltration, and tumor mutation burden. Subsequently, we assessed the relationship between the risk score and the sensitivity to various immunotherapies and anticancer drugs. We identified 14 blood metabolites at the molecular level that have a causal relationship with bladder tumors. At the gene level, the study discussed differentially expressed GM genes in MIBC. First, we established a risk model predicting overall survival (OS) based on GM genes, confirming its reliable predictive ability in MIBC patients and validated it in a GEO cohort. Additionally, a reliable column line chart was created. Secondly, two distinct molecular subtypes were identified, and the associations between different risk groups and tumor microenvironment and immune infiltration were observed. In addition, the predicted risk values correlated with responses to a broad range of pharmaceutical agents. In summary, we confirmed the causal relationship between blood metabolites and bladder tumors. Furthermore, a risk scoring model related to glutamine metabolism consisting of 9 genes was developed. This model could potentially serve as a useful tool for predicting prognosis and guiding the treatment of MIBC patients.

中文翻译：

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利用谷氨酰胺代谢开发肌肉浸润性膀胱癌的预后模型

肌层浸润性膀胱癌（MIBC）的特点是其明显的侵袭性和不良的预后。免疫疗法和靶向治疗已成为各种类型癌症的关键治疗选择。代谢改变是癌细胞的一个决定性特征，越来越多的证据表明谷氨酰胺代谢 (GM) 在肿瘤代谢中发挥着重要作用。然而，GM 与 MIBC 临床结果、免疫微环境和免疫治疗之间的关系仍不清楚。本研究采用孟德尔随机化来探讨血液代谢物与膀胱肿瘤之间的因果关系。我们系统地评估了 373 个谷氨酰胺代谢相关基因，并鉴定了预后相关基因，从而构建了谷氨酰胺相关预后模型。进一步分析证实了高风险组和低风险组与肿瘤微环境、免疫细胞浸润和肿瘤突变负荷的相关性。随后，我们评估了风险评分与对各种免疫疗法和抗癌药物的敏感性之间的关系。我们在分子水平上鉴定出了 14 种与膀胱肿瘤存在因果关系的血液代谢物。在基因水平上，该研究讨论了 MIBC 中差异表达的 GM 基因。首先，我们建立了一个基于GM基因预测总生存期（OS）的风险模型，证实了其对MIBC患者的可靠预测能力，并在GEO队列中进行了验证。此外，还创建了可靠的柱线图。其次，确定了两种不同的分子亚型，并观察了不同风险组与肿瘤微环境和免疫浸润之间的关联。此外，预测的风险值与对多种药剂的反应相关。总之，我们证实了血液代谢物与膀胱肿瘤之间的因果关系。此外，还开发了由9个基因组成的与谷氨酰胺代谢相关的风险评分模型。该模型有可能成为预测 MIBC 患者预后和指导治疗的有用工具。