Dataset Information

Clinical Significance and Tumor Microenvironment Characterization of a Novel Immune-Related Gene Signature in Bladder Cancer.

ABSTRACT: Cancer immunotherapy plays a crucial role in bladder cancer (BC) progression. Increasing evidence has elucidated the clinicopathologic significance of the tumor microenvironment (TME) in predicting outcomes and therapeutic efficacy. This study sought to establish a comprehensive analysis of the immune-gene signature combined with TME to assist in BC prognosis. We selected sixteen immune-related genes (IRGs) after a weighted gene co-expression network and survival analysis. Enrichment analysis revealed that these IRGs were actively involved in Mitophagy and Renin secretion pathways. After multivariable COX analysis, the IRGPI comprising NCAM1, CNTN1, PTGIS, ADRB3, and ANLN was established to predict the overall survival of BC, which was validated in both TCGA and GSE13507 cohorts. In addition, a TME gene signature was developed for molecular and prognosis subtyping with unsupervised clustering, followed by a panoramic landscape characterization of BC. In summary, the IRGPI model developed in our study provided a valuable tool with an improved prognosis for BC.

SUBMITTER: Wang Z

PROVIDER: S-EPMC10003605 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Clinical Significance and Tumor Microenvironment Characterization of a Novel Immune-Related Gene Signature in Bladder Cancer.

Wang Zhaohui Z Wang Tao T Wu Gangfeng G Zhu Lei L Zhang Jian J

Journal of clinical medicine 20230227 5

Cancer immunotherapy plays a crucial role in bladder cancer (BC) progression. Increasing evidence has elucidated the clinicopathologic significance of the tumor microenvironment (TME) in predicting outcomes and therapeutic efficacy. This study sought to establish a comprehensive analysis of the immune-gene signature combined with TME to assist in BC prognosis. We selected sixteen immune-related genes (IRGs) after a weighted gene co-expression network and survival analysis. Enrichment analysis re ...[more]

PMID: 36902678

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Project description:BackgroundUrothelial carcinoma of the bladder (UCB) is the most prevalent malignant tumor of the urinary system worldwide, which has a significant recurrence rate despite multiple treatment options available. As a unique and novel copper-dependent programmed cell death mechanism, the comprehensive impact of cuproptosis on the tumor immune microenvironment, clinicopathological characteristics and the prognosis of patients remains largely unclear.MethodsA total of 568 UCB samples were thoroughly examined for cuproptosis patterns using data downloaded from TCGA and GEO, based on 10 cuproptosis-related genes reported previously. Then, the univariate COX regression analysis was performed on the genes that differed across the various patterns. To measure individual cuproptosis pattern, a cuproptosis score system was constructed using a principal component analysis algorithm. To validate the scoring system, immunohistochemical staining was performed on tumor tissues with different pathological grades, and experiments in vitro were conducted about the differentially expressed genes related to prognosis. Finally, the capacity of scoring system to predict the response to immunotherapy was verified by using data from IMvigor 210 cohort.ResultsFour unique cuproptosis clusters and two gene clusters were finally found by the investigation. The clinical features and prognosis of patients, as well as the mRNA transcriptome, pathway enrichment, and immune cell infiltration in TME, varied dramatically between various cuproptosis clusters and gene clusters. To identify individual cuproptosis patterns in UCB patients, we also established a cuproptosis scoring system. After validation with multiple methods, it was indicated that the score system could predict the prognosis of UCB patients and was significantly connected to clinical features such TNM category, tumor grade, molecular type and ultimate survival status. The clinical outcomes of UCB patients were predicted effectively according to the tumor mutation burden in conjunction with the scoring system. Furthermore, we found that the cuproptosis score had a significant correlation with the response to immunotherapy and the sensitivity to chemotherapy.ConclusionThis study revealed the potential impact of cuproptosis on the UCB tumor immune microenvironment and clinical pathological characteristics. The cuproptosis score system could effectively predict the prognosis of patients and the response to chemotherapy and immunotherapy.

Project description:BackgroundOsteosarcoma is a malignant tumor that usually occurs in adolescents aged 10-20 years and is associated with poor prognosis. Ferroptosis is an iron-dependent cell death mechanism that plays a vital role in cancer.MethodsOsteosarcoma transcriptome data were downloaded from the public database TARGET and from previous studies. A prognostic risk score signature was constructed using bioinformatics analysis, and its efficacy was determined by analyzing typical clinical features. The prognostic signature was then validated with external data. Differences in immune cell infiltration between high- and low-risk groups were analyzed. The potential of the prognostic risk signature as a predictor of immunotherapy response was evaluated using the GSE35640 (melanoma) dataset. Five key genes expression were measured by real-time PCR and western blot in human normal osteoblasts and osteosarcoma cells. Moreover, malignant biological behaviors of osteosarcoma cells were tested by modulating gene expression level.ResultsWe obtained 268 ferroptosis-related genes from the online database FerrDb and published articles. Transcriptome data and clinical information of 88 samples in the TARGET database were used to classify genes into two categories using clustering analysis, and significant differences in survival status were identified. Differential ferroptosis-related genes were screened, and functional enrichment showed that they were associated with HIF-1, T cells, IL17, and other inflammatory signaling pathways. Prognostic factors were identified by univariate Cox regression and LASSO analysis, and a 5-factor prognostic risk score signature was constructed, which was also applicable for external data validation. Experimental validation indicated that the mRNA and protein expression level of MAP3K5, LURAP1L, HMOX1 and BNIP3 decreased significantly, though meanwhile MUC1 increased in MG-63 and SAOS-2 cells compared with hFOB1.19 cells. Cell proliferation and migration ability of SAOS-2 were affected based on alterations of signature genes.ConclusionsSignificant differences in immune cell infiltration between high- and low-risk groups indicated that the five ferroptosis-related prognostic signature was constructed and could be used to predict the response to immunotherapy in osteosarcoma.

Project description:The intricate nature and varied forms of bladder urothelial carcinoma (BLCA) highlight the need for new indicators to define tumor prognosis. Disulfidptosis, a novel form of cell death, is closely linked to BLCA progression, prognosis, and treatment outcomes. Our current goal is to develop a novel disulfidptosis-related immune prognostic model to enhance BLCA treatment strategies. Utilizing RNA-seq data from The Cancer Genome Atlas (TCGA) , which included 419 patients (19 normal, 400 tumor), we performed weighted gene co-expression network analysis (WGCNA) to identify disulfidptosis-associated immune genes. Through multivariate Cox regression, and the least absolute shrinkage and selection operator (LASSO) regularization, we established a disulfidptosis-related immune risk scoring system. A nomogram combining risk score and clinical features predicted prognosis. Model performance was validated through survival curve analysis and independent validation cohort. Immune checkpoints, cell infiltration, and tumor mutation load were assessed. Differential gene enrichment analysis was conducted. Prognostic genes were validated via in vitro experiments. Eight immune genes related to disulfidptosis were identified and verified in BLCA prognosis. A prognostic model outperformed previous ones in predicting overall survival (OS) for high- and low-risk groups. Patients with low-risk scores had higher OS rates and tumor mutation burden (TMB) compared to high-risk score patients. CD4 memory T cells, CD8 T cells, M1 macrophages, and resting NK cells were found to be higher in the low-risk group. Immune checkpoint inhibitor (ICI) treatment may be more effective for the low-risk score group. High-risk score group exhibited stronger correlation with cancer malignant pathways. Knocking out tumor necrosis factor receptor superfamily member 12 A (TNFRSF12A) inhibits BLCA cell proliferation and invasion while overexpressing it has the opposite effect. We constructed a novel risk score model that combines disulfidptosis and immune genes, demonstrating good prognostic prediction performance. We discovered and verified that the TNFRSF12A gene is an oncogene in BLCA, which may help provide personalized guidance for individualized treatment and immunotherapy selection for BLCA patients to a certain extent.

Dataset Information

Clinical Significance and Tumor Microenvironment Characterization of a Novel Immune-Related Gene Signature in Bladder Cancer.

Publications

Clinical Significance and Tumor Microenvironment Characterization of a Novel Immune-Related Gene Signature in Bladder Cancer.

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