通过基因组分析揭示膀胱癌中铜死亡的预后及肿瘤微环境特征

Revealing prognostic and tumor microenvironment characteristics of cuproptosis in bladder cancer by genomic analysis.

作者信息

Zhang Shun, Yu Shenggen, Duan Huangqi, Xia Weimin, Wang Chen, Shen Haibo

机构信息

Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

出版信息

Front Genet. 2022 Oct 3;13:997573. doi: 10.3389/fgene.2022.997573. eCollection 2022.

Abstract

Bladder cancer (BLCA) is the most common malignant tumor in the urinary system, while the prognosis of muscle-invasive bladder cancer (MIBC) is poor. Cuproptosis might be a promising therapeutic approach to trigger tumor cell death. This study aimed to figure out the role of cuproptosis in BLCA and constructed a new cuproptosis scoring system to guide clinical diagnosis and individualize treatments. Consensus clustering was used to classify 490 patients with BLCA from TCGA and GEO cohorts. Survival outcomes and functional enrichment analyses were performed between the different subtypes. The cuproptosis scoring system was constructed by LASSO-Cox analysis. ESTIMATE, CIBERSORT, and ssGSEA were used to investigate the tumor microenvironment (TME). Drug sensitivity was evaluated with pRRophetic. An immunotherapy cohort was used to investigate the treatment response. The cuproptosis scoring system was verified in our own cohort with quantitative real-time PCR. An overview of 12 cuproptosis genes (CuGs) in the TCGA database was depicted. Based on the mRNA expression profiles of CuGs, patients were classified into two cuproptosis molecular patterns. Based on the differential genes between the two cuproptosis patterns, the patients were classified into two cuproptosis gene clusters. There were distinct survival outcomes, signaling pathways, and TME between the two subtypes. A 7-gene cuproptosis scoring system was constructed. Patients with high cuproptosis scores showed worse OS and more immunosuppressing TME than those with low cuproptosis scores. The two cuproptosis score groups had distinct mutation profiles. Patients with high cuproptosis scores tended to be sensitive to chemotherapy drugs, but insensitive to immune checkpoint inhibitors (ICIs) treatment. This study depicted the landscape of cuproptosis in BLCA. We constructed a cuproptosis scoring system to predict the prognosis of BLCA patients. There were significant differences in survival outcomes, TME, mutation profiles, and drug sensitivities in high and low cuproptosis score patients. The cuproptosis scoring system could help oncologists comprehensively understand the tumor characteristic of BLCA and make individualized treatment strategies.

摘要

膀胱癌(BLCA)是泌尿系统中最常见的恶性肿瘤,而肌层浸润性膀胱癌(MIBC)的预后较差。铜死亡可能是一种引发肿瘤细胞死亡的有前景的治疗方法。本研究旨在明确铜死亡在BLCA中的作用,并构建一种新的铜死亡评分系统以指导临床诊断和个体化治疗。采用共识聚类方法对来自TCGA和GEO队列的490例BLCA患者进行分类。对不同亚型之间的生存结果和功能富集分析。通过LASSO-Cox分析构建铜死亡评分系统。使用ESTIMATE、CIBERSORT和ssGSEA研究肿瘤微环境(TME)。用pRRophetic评估药物敏感性。使用免疫治疗队列研究治疗反应。通过定量实时PCR在我们自己的队列中验证铜死亡评分系统。描绘了TCGA数据库中12个铜死亡基因(CuGs)的概况。基于CuGs的mRNA表达谱,将患者分为两种铜死亡分子模式。根据两种铜死亡模式之间的差异基因,将患者分为两个铜死亡基因簇。两种亚型之间存在明显的生存结果、信号通路和TME差异。构建了一个7基因铜死亡评分系统。铜死亡评分高的患者与评分低的患者相比,总生存期更差,TME免疫抑制更强。两个铜死亡评分组具有不同的突变谱。铜死亡评分高的患者倾向于对化疗药物敏感,但对免疫检查点抑制剂(ICIs)治疗不敏感。本研究描绘了BLCA中铜死亡的全貌。我们构建了一个铜死亡评分系统来预测BLCA患者的预后。铜死亡评分高和低的患者在生存结果、TME、突变谱和药物敏感性方面存在显著差异。铜死亡评分系统可以帮助肿瘤学家全面了解BLCA的肿瘤特征并制定个体化治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b44a/9575963/108a644cf240/fgene-13-997573-g001.jpg

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