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A circadian rhythm-related gene signature associated with tumor immunity, cisplatin efficacy, and prognosis in bladder cancer.

ABSTRACT: Circadian dysregulation involves malignant tumor initiation and progression, but the understanding of circadian rhythm's roles in bladder cancer (BCa) remains insufficient. The circadian rhythm-related genes were collected and clustered based on the Cancer Genome Atlas (TCGA), and the clustering was significantly associated with the prognosis and risk clinicopathological features. Through genomic difference analysis and gene pairing, a circadian rhythm-related signature was successfully established. Kaplan-Meier survival analysis and time-dependent receiver operating curves displayed that the prognosis model was a reliable prognosis biomarker both in the training cohort (n = 396, P = 2.687e-10) and external validation cohort (n = 224, P = 1.45e-02). The patients with high risk have high immune infiltration and high expression of immune checkpoint genes, which partly account for the poor prognosis. TIDE algorithm and the validation in IMvigor210 cohort indicated that the risk signature was a promising marker for the immunotherapeutic response. The risk model could also predict the therapeutic response of cisplatin, which was validated in the Genomics of Drug Sensitivity in Cancer database (P = 0.0049), TCGA (P = 0.038), and T24 BCa cells treated with cisplatin. The functional enrichment showed the risk model was significantly correlated with some malignant phenotypes, such as angiogenesis, epithelial-mesenchymal transition, and KRAS signaling pathway. Totally, we proposed a novel circadian rhythm-related signature for prognosis evaluation, which also helped to predict the immune infiltration and cisplatin sensitivity in BCa.

SUBMITTER: Zhou R

PROVIDER: S-EPMC8714136 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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A circadian rhythm-related gene signature associated with tumor immunity, cisplatin efficacy, and prognosis in bladder cancer.

Zhou Ranran R Chen Xinyu X Liang Jingjing J Chen Qi Q Tian Hu H Yang Cheng C Liu Cundong C

Aging 20211203 23

Circadian dysregulation involves malignant tumor initiation and progression, but the understanding of circadian rhythm's roles in bladder cancer (BCa) remains insufficient. The circadian rhythm-related genes were collected and clustered based on the Cancer Genome Atlas (TCGA), and the clustering was significantly associated with the prognosis and risk clinicopathological features. Through genomic difference analysis and gene pairing, a circadian rhythm-related signature was successfully establis ...[more]

PMID: 34862329

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Project description:BackgroundCuproptosis is a newly identified form of cell death that is dependent on copper (Cu) ions, termed Cu-dependent cytotoxicity. This process is distinct from other forms of cell death such as apoptosis, necrosis, and ferroptosis. The accumulation of copper is known to play a significant role in various biological processes, including angiogenesis (the formation of new blood vessels) and metastasis (the spread of cancer cells to different parts of the body). These processes are crucial for tumor growth and progression, indicating that copper and the cuproptosis-related genes (CPRGs) might be indispensable in the context of cancer development and progression. Given this background, we aimed to explore the relationship between CPRGs and both prognostic predictions and tumor microenvironment (TME) infiltration in bladder cancer (BLCA).MethodsFor this study, we utilized data from The Cancer Genome Atlas (TCGA) to identify CPRGs and subsequently divided BLCA patients into three distinct molecular clusters based on these genes. To assess the proportions of various immune cell types within the TME, we employed single-sample gene set enrichment analysis (ssGSEA) and the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) method. These computational techniques allowed us to quantify the infiltration of different immune cells, providing insights into the immune landscape of the tumors. Furthermore, we developed a risk score model using CPRGs to predict the survival prospects of BLCA patients.ResultsOur analysis identified three molecular clusters of BLCA patients, each exhibiting unique clinical features and patterns of TME infiltration. Among these clusters, cluster 1 was associated with a poor prognosis. Interestingly, this cluster also showed significant infiltration of activated CD4+ (ssGSEA P<0.001) and CD8+ T (ssGSEA P<0.05) cells, which are crucial components of the immune response against tumors. This finding suggests a complex interaction between the immune system and the tumor, where a high presence of T cells does not necessarily correlate with better outcomes. Additionally, our risk score model revealed that the high-risk group, characterized by a specific expression pattern of CPRGs, also had enhanced infiltration of CD4+ and CD8+ T cells. This indicates that the cuproptosis-based risk model has a robust ability to predict patient prognosis and can guide immunotherapy decisions.ConclusionsOur study sheds light on the biological functions of CPRGs within the TME of BLCA and their correlations with clinical parameters and patient prognosis. The identification of distinct molecular clusters with varying prognoses and immune cell infiltrations highlights the heterogeneity of BLCA and underscores the potential of CPRGs as biomarkers for prognosis and therapeutic targets. These findings offer new perspectives for the development of immunotherapeutic strategies in the treatment of BLCA patients, potentially leading to more personalized and effective cancer therapies.

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Dataset Information

A circadian rhythm-related gene signature associated with tumor immunity, cisplatin efficacy, and prognosis in bladder cancer.

Publications

A circadian rhythm-related gene signature associated with tumor immunity, cisplatin efficacy, and prognosis in bladder cancer.

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