Prognosis stratification and personalized treatment in bladder cancer through a robust immune gene pair-based signature.
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ABSTRACT:
SUBMITTER: Lu X
PROVIDER: S-EPMC8214857 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Prognosis stratification and personalized treatment in bladder cancer through a robust immune gene pair-based signature.
Lu Xiaofan X Meng Jialin J Zhu Junkai J Zhou Yujie Y Jiang Liyun L Wang Yang Y Wen Weiheng W Liang Chaozhao C Yan Fangrong F
Clinical and translational medicine 20210601 6
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Project description:BackgroundBladder cancer is the second most common malignant tumor in the urogenital system. The research investigated the prognostic role of immune-related long non-coding RNA (lncRNA) in bladder cancer.MethodsWe extracted 411 bladder cancer samples from The Cancer Genome Atlas database. Single-sample gene set enrichment analysis was employed to assess the immune cell infiltration of these samples. We recognized differentially expressed lncRNAs between tumors and paracancerous tissues, and differentially expressed lncRNAs between the high and low immune cell infiltration groups. Venn diagram analysis detected differentially expressed lncRNAs that intersected the above groups. LncRNAs with prognostic significance were identified by regression analysis. Multivariate Cox analysis was used to establish the risk score model. Then we established and evaluated the nomogram. Additionally, we performed gene set enrichment analysis to explore the potential functions of the screened lncRNAs in tumor pathogenesis.ResultsThree hundred and twenty differentially expressed lncRNAs were recognized. We randomly divided patients into the training data set and the testing data set at a 2: 1 ratio. In the training data set, 9 immune-related lncRNAs with prognostic significance were identified. The risk score model was constructed to classify patients as high- and low-risk cohorts. Patients in the low-risk cohort had better survival outcomes than those in the high-risk cohort. The nomogram was established based on the indicators including age, gender, tumor-node-metastases stage, and risk score. The model's predictive performance was confirmed by the receiver operating characteristic curve analysis, concordance index method, calibration curve, and decision curve analysis. The testing data set also achieved similar results. Bioinformatics analysis suggested that the 9-lncRNA signature was involved in the modulation of various immune responses, antigen processing and presentation, and T cell receptor signaling pathway.ConclusionsOur study uncovered the prognostic value of immune-related lncRNAs for bladder cancer and showed that they may regulate tumor pathogenesis in various ways.
| S-EPMC8446409 | biostudies-literature
Project description:Immunotherapy has been a milestone for muscle-invasive bladder cancer (MIBC), but only a small portion of patients can benefit from it. Therefore, it is crucial to develop a robust individualized immune-related signature of MIBC to identify patients potentially benefiting from immunotherapy. The current study identified patients from the Cancer Genome Atlas (TCGA) and immune genes from the ImmPort database, and used improved data analytical methods to build up a 45 immune-related gene pair signature, which could classify patients into high-risk and low-risk groups. The signature was then independently validated by a Gene Expression Omnibus (GEO) dataset and IMvigor210 data. The subsequent analysis confirmed the worse survival outcomes of the high-risk group in both training (p < 0.001) and validation cohorts (p = 0.018). A signature-based risk score was proven to be an independent risk factor of overall survival (p < 0.001) and could predict superior clinical net benefit compared to other clinical factors. The CIBERSORT algorithm revealed the low-risk group had increased CD8+ T cells plus memory-activated CD4+ T-cell infiltration. The low-risk group also had higher expression of PDCD1 (PD-1), CD40, and CD27, and lower expression of CD276 (B7-H3) and PDCD1LG2 (PD-L2). Importantly, IMvigor210 data indicated that the low-risk group had higher percentage of "inflamed" phenotype plus less "desert" phenotype, and the survival outcomes were significantly better for low-risk patients after immunotherapy (p = 0.014). In conclusion, we proposed a novel and promising prognostic immune-related gene pair (IRGP) signature of MIBC, which could provide us a panoramic view of the tumor immune microenvironment of MIBC and independently identify MIBC patients who might benefit from immunotherapy.
| S-EPMC8664435 | biostudies-literature
Project description:Bladder cancer (BC) is a commonly occurring malignant tumor affecting the urinary tract. Zinc finger proteins (ZNFs) constitute the largest transcription factor family in the human genome and are therefore attractive biomarker candidates for BC prognosis. In this study, we profiled the expression of ZNFs in The Cancer Genome Atlas (TCGA) BC cohort and developed a novel prognostic signature based on 7 ZNF-coding genes. After external validation of the model in the GSE48276 dataset, we integrated the 7-ZNF-gene signature with patient clinicopathological data to construct a nomogram that forecasted 1-, 2-, and 3-year OS with good predictive accuracy. We then accessed The Genomics of Drug Sensitivity in Cancer database to predict the therapeutic drug responses of signature-defined high- and low-risk BC patients in the TCGA cohort. Greater sensitivity to chemotherapy was revealed in the low-risk group. Finally, we conducted gene set enrichment analysis of the signature genes and established, by applying the ESTIMATE algorithm, distinct correlations between the two risk groups and the presence of stromal and immune cell types in the tumor microenvironment. By allowing effective risk stratification of BC patients, our novel ZNF gene signature may enable tailoring more intensive treatment for high-risk patients.
| S-EPMC8148496 | biostudies-literature
Project description:TP53 is the most frequently mutated gene in muscle invasive bladder cancer (MIBC) and there are two gene signatures regarding TP53 developed for MIBC prognosis. However, they are limited to immune genes only and unable to be used individually across platforms due to their quantitative manners. We used 827 gene expression profiles from seven MIBC cohorts with varied platforms to build a pairwise TP53-derived transcriptome signature, 13 gene pairs (13-GPs). Since the 13-GPs model is a single sample prognostic predictor, it can be applied individually in practice and is applicable to any gene-expression platforms without specific normalization requirements. Survival difference between high-risk and low-risk patients stratified by the 13-GPs test was statistically significant (HR range: 2.26-2.76, all P < .0001). Discovery and validation sets showed that the 13-GPs was an independent prognostic factor after adjusting other clinical features (HR range: 2.21-2.82, all P < .05). Moreover, it was a potential supplement to the consensus molecular classification of MIBC to further stratify the LumP subtype (patients with better prognoses). High- and low-risk patients by the 13-GPs model presented distinct immune microenvironment and DDR mutation rates, suggesting that it might have the potential for immunotherapy. Being a general approach to other cancer types, this study demonstrated how we integrated gene variants with pairwise gene panels to build a single sample prognostic test in translational oncology.
| S-EPMC9873666 | biostudies-literature
Project description:BackgroundThe close relationship between histone deacetylase 9 (HDAC9) and immunity has attracted attention. We constructed an immune signature for HDAC9, a vital epigenetic modification, to predict the survival status and treatment benefits in bladder cancer (BC).MethodsAn exhaustive analysis of HDAC9 and immunology via the tumor and immune system interaction database (TISIDB) was performed, and an immune prognostic risk signature was developed based on genes enriched in the top five immune-related pathways under high HDAC9 status. Comprehensive analysis of survival curves and Cox regression were used to estimate the effectiveness of the risk signature. The relationship between immunological characteristics and the risk score was evaluated, and the mechanisms were also explored.ResultsIn the TISIDB, HDAC9 was closely related to various immunological characteristics. The risk signature was obtained based on genes related to prognosis enriched in the top five immune-related pathways under high HDAC9 status. The survival rate of the high-risk BC patients was poor. The risk score was closely related to multiple immunological characteristics, drug sensitivity, immunotherapy benefits and biofunctions.ConclusionAn immune-related prognostic signature established for HDAC9 expression status could independently predict the prognosis of BC patients. The use of this signature could help clinicians make personalized treatment decisions.
| S-EPMC8893690 | biostudies-literature
Project description:Tumor microenvironment (TME) has critical impacts on the pathogenesis of lung adenocarcinoma (LUAD). However, the molecular mechanism of TME effects on the prognosis of LUAD patients remains unclear. Our study aimed to establish an immune-related gene pair (IRGP) model for prognosis prediction and internal mechanism investigation. Based on 702 TME-related differentially expressed genes (DEGs) extracted from The Cancer Genome Atlas (TCGA) training cohort using the ESTIMATE algorithm, a 10-IRGP signature was established to predict LUAD patient prognosis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that DEGs were significantly associated with tumor immune response. In both TCGA training and Gene Expression Omnibus validation datasets, the risk score was an independent prognostic factor for LUAD patients using Lasso-Cox analysis, and patients in the high-risk group had poorer prognosis than those in the low-risk one. In the high-risk group, M2 macrophage and neutrophil infiltrations were higher, while the levels of T cell follicular helpers were significantly lower. The gene set enrichment analysis results showed that DNA repair signaling pathways were involved. In summary, we established an IRGP signature as a potential biomarker to predict the prognosis of LUAD patients.
| S-EPMC7873765 | biostudies-literature
Project description:A substantial proportion of prostatic adenocarcinoma (PRAD) patients experience biochemical failure (BCF) after radical prostatectomy (RP). The immune microenvironment plays a vital role in carcinogenesis and the development of PRAD. This study aimed to identify a novel immune-related gene (IRG)-based signature for risk stratification and prognosis of BCF in PRAD. Weighted gene coexpression network analysis was carried out to identify a BCF-related module in a discovery cohort of patients who underwent RP at the Massachusetts General Hospital. The median follow-up time was 70.32 months. Random forest and multivariate stepwise Cox regression analyses were used to identify an IRG-based signature from the specific module. Risk plot analyses, Kaplan-Meier curves, receiver operating characteristic curves, univariate and multivariate Cox regression analyses, stratified analysis, and Harrell's concordance index were used to assess the prognostic value and predictive accuracy of the IRG-based signature in the internal discovery cohort; The Cancer Genome Atlas database was used as a validation cohort. Tumor immune estimation resource database analysis and CIBERSORT algorithm were used to assess the immunophenotype of PRAD. A novel IRG-based signature was identified from the specific module. Five IRGs (BUB1B, NDN, NID1, COL4A6, and FLRT2) were verified as components of the risk signature. The IRG-based signature showed good prognostic value and predictive accuracy in both the discovery and validation cohorts. Infiltrations of various immune cells were significantly different between low-risk and high-risk groups in PRAD. We identified a novel IRG-based signature that could function as an index for assessing tumor immune status and risk stratification in PRAD.
| S-EPMC8486177 | biostudies-literature
Project description:Immune-related genes (IRGs) are closely related to tumor progression and the immune microenvironment. Few studies have investigated the effect of tumor immune microenvironment on the survival and response to immune checkpoint inhibitors of patients with bladder urothelial carcinoma (BLCA). We constructed two IRG-related prognostic signatures based on gene-immune interaction for predicting risk stratification and immunotherapeutic responses. We also verified their predictive ability on internal and overall data sets. Patients with BLCA were divided into high- and low-risk groups. The high-risk group had poor survival, enriched innate immune-related cell subtypes, low tumor mutation burden, and poor response to anti-PD-L1 therapy. Our prognostic signatures can be used as reliable prognostic biomarkers, which may be helpful to screen the people who will benefit from immunotherapy and guide the clinical decision-making of patients with BLCA.
| S-EPMC8739239 | biostudies-literature
Project description:Background: A growing amount of evidence has suggested the clinical importance of stromal and immune cells in the gastric cancer microenvironment. However, reliable prognostic signatures based on assessments of stromal and immune components have not been well-established. This study aimed to develop a stromal-immune score-based gene signature in gastric cancer. Methods: Stromal and immune scores were estimated from transcriptomic profiles of a gastric cancer cohort from TCGA using the ESTIMATE algorithm. A robust partial likelihood-based Cox proportional hazard regression model was applied to select prognostic genes and to construct a stromal-immune score-based gene signature. Two independent datasets from GEO were used for external validation. Results: Favorable overall survivals were found in patients with high stromal score (p = 0.014) and immune score (p = 0.045). Forty-five stromal-immune score-related differentially expressed genes were identified. Using a robust partial likelihood-based Cox proportional hazard regression model, a gene signature containing SOX9, LRRC32, CECR1, and MS4A4A was identified to develop a risk stratification model. Multivariate analysis revealed that the stromal-immune risk score was an independent prognostic factor (p = 0.018). Based on the risk stratification model, the cohort was classified into three groups yielding incremental survival outcomes (log-rank test p = 0.0004). A nomogram integrating the risk stratification model and clinicopathologic factors was developed. Calibration and decision curves showed a better performance and net benefits for the nomogram. Similar findings were validated in two independent cohorts. Conclusion: The stromal-immune score-based gene signature represents a prognosis stratification tool in gastric cancer.
| S-EPMC6861210 | biostudies-literature
Project description:BackgroundBladder cancer (BC) is the ninth most common malignant tumor. We constructed a risk signature using immune-related gene pairs (IRGPs) to predict the prognosis of BC patients.MethodsThe mRNA transcriptome, simple nucleotide variation and clinical data of BC patients were downloaded from The Cancer Genome Atlas (TCGA) database (TCGA-BLCA). The mRNA transcriptome and clinical data were also extracted from Gene Expression Omnibus (GEO) datasets (GSE31684). A risk signature was built based on the IRGPs. The ability of the signature to predict prognosis was analyzed with survival curves and Cox regression. The relationships between immunological parameters [immune cell infiltration, immune checkpoints, tumor microenvironment (TME) and tumor mutation burden (TMB)] and the risk score were investigated. Finally, gene set enrichment analysis (GSEA) was used to explore molecular mechanisms underlying the risk score.ResultsThe risk signature utilized 30 selected IRGPs. The prognosis of the high-risk group was significantly worse than that of the low-risk group. We used the GSE31684 dataset to validate the signature. Close relationships were found between the risk score and immunological parameters. Finally, GSEA showed that gene sets related to the extracellular matrix (ECM), stromal cells and epithelial-mesenchymal transition (EMT) were enriched in the high-risk group. In the low-risk group, we found a number of immune-related pathways in the enriched pathways and biofunctions.ConclusionsWe used a new tool, IRGPs, to build a risk signature to predict the prognosis of BC. By evaluating immune parameters and molecular mechanisms, we gained a better understanding of the mechanisms underlying the risk signature. This signature can also be used as a tool to predict the effect of immunotherapy in patients with BC.
| S-EPMC8281685 | biostudies-literature