Molecular subtypes and response to immunotherapy in bladder cancer patients.
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ABSTRACT:
SUBMITTER: Todenhofer T
PROVIDER: S-EPMC6642947 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
Molecular subtypes and response to immunotherapy in bladder cancer patients.
Todenhöfer Tilman T Seiler Roland R
Translational andrology and urology 20190701 Suppl 3
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Project description:BackgroundThe purpose of this study was to identify the ferroptosis-related molecular subtypes in muscle invasive bladder cancer (MIBC) associated with the tumor microenvironment (TME) and immunotherapy.MethodsExpression profiles and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) dataset. Nonnegative matrix factorization (NMF) analysis was performed to identify two molecular subtypes based on 41 ferroptosis-related prognostic genes. The differences between the two subtypes were compared in terms of prognosis, somatic mutations, gene ontology (GO), cytokines, pathways, immune cell infiltrations, stromal/immune scores, tumor purity and response to immunotherapy. We also constructed a risk prediction model using multivariate Cox regression analysis to analyze survival data based on differentially expressed genes (DEGs) between subtypes. In combination with clinicopathological features, a nomogram was constructed to provide a more accurate prediction for overall survival (OS).ResultsTwo molecular subtypes (C1 and C2) of MIBC were identified according to the expression of ferroptosis-related genes. The C2 subtype manifested poor prognosis, high enrichment in the cytokine-cytokine receptor interaction pathway, high abundance of immune cell infiltration, immune/stromal scores and low tumor purity. Additionally, C2 is less sensitive to immunotherapy. The risk prediction model based on five pivotal genes (SLC1A6, UPK3A, SLC19A3, CCL17 and UGT2B4) effectively predicted the prognosis of MIBC patients.ConclusionsA novel MIBC classification approach based on ferroptosis-related gene expression profiles was established to provide guidance for patients who are more sensitive to immunotherapy. A nomogram with a five-gene signature was built to predict the prognosis of MIBC patients, which would be more accurate when combined with clinical factors.
| S-EPMC9745360 | biostudies-literature
Project description:Currently, only a limited set of molecular traits are utilized to direct treatment for metastatic CRC (mCRC). The molecular classification of CRC depicts tumor heterogeneity based on gene expression patterns and aids in comprehending the biological characteristics of tumor formation, growth and prognosis. Additionally, it assists physicians in tailoring the therapeutic approach. Microsatellite instability (MSI-H)/deficient mismatch repair proteins (MMRd) status has become a ubiquitous biomarker in solid tumors, caused by mutations or methylation of genes and, in turn, the accumulation of mutations and antigens that subsequently induce an immune response. Immune checkpoint inhibitors (ICI) have recently received approval for the treatment of mCRC with MSI-H/MMRd status. However, certain individuals experience either initial or acquired resistance. The tumor-programmed cell death ligand 1 (PD-L1) has been linked to the ability of CRC to evade the immune system and promote its growth. Through comprehensive research conducted via the PUBMED database, the objectives of this paper were to review the molecular characteristics linked to tumor response in metastatic CRC in light of improved patients' outcomes following ICI therapies as seen in clinical trials and to identify particular microRNAs that can modulate the expression of specific oncoproteins, such as PD-L1, and disrupt the mechanisms that allow the immune system to be evaded.
| S-EPMC10972200 | biostudies-literature
Project description:Background Bladder cancer (BC) is a disease with significant heterogeneity and poor prognosis. The prognosis and therapeutic response of BC patients are significantly influenced by endothelial cells in the tumor microenvironment. In order to understand BC from the perspective of endothelial cells, we orchestrated molecular subtypes and identified key genes. Methods Single-cell and bulk RNA sequencing data were extracted from online databases. R and its relative packages were used to analyze these data. Cluster analysis, prognostic value analysis, function analysis, immune checkpoints, tumor immune environment and immune prediction were conducted. Results Five endothelial-related genes (CYTL1, FAM43A, HSPG2, RBP7, and TCF4) divided BC patients in the TCGA, GSE13507, and GSE32894 datasets into two clusters, respectively. In prognostic value analysis, patients in the cluster 2 were substantially associated with worse overall survival than those in the cluster 1 according to the results of TCGA, GSE13507 and GSE32894 datasets. In the results of functional analysis, the endothelial-related clusters was enriched in immune-related, endothelial-related and metabolism-related pathways. Samples in the cluster 1 had a statistically significant increase in CD4+ T cells and NK-cell infiltration. Cluster 1 was positively correlated with the cancer stem score and tumor mutational burden score. The results of immune prediction analysis indicated that 50.6% (119/235) of patients in the cluster 1 responded to immunotherapy, while the response rate in the cluster 2 decreased to 16.7% (26/155). Conclusion In this study, we categorized and discovered distinctive prognosis-related molecular subtypes and key genes from the perspective of endothelial cells at the genetic level by integrating single-cell and bulk RNA sequencing data, primarily to provide a roadmap for precision medicine.
| S-EPMC10070733 | biostudies-literature
Project description:In 2014, there was a burst of studies on the molecular subtypes of bladder cancer in the published literature that was made possible by the advances in high-throughput technologies. Based on gene expression profiling, the major molecular classification subdivisions were basal and luminal subtypes, which resembled to those observed in breast cancers. These basal and luminal subtypes were further subdivided by TCGA into squamous, infiltrated, luminal-papillary, luminal/genomically unstable (GU), and neuronal/small cell carcinoma (SCC) subtypes. Recently, an international subtypes consensus project further expanded on the TCGA subtypes by defining a consensus molecular classification (CMC). A multidisciplinary team of experts generated CMC to overcome the difficulties of clinical applications due to several published bladder cancer molecular classifications with various nomenclatures and molecular features. It included six molecular subtypes with the addition of one more luminal subtype (luminal nonspecified) compared to the TCGA subtype classification. The initial research efforts have focused on the characterization of each subtype at the molecular and histopathologic levels, but more recent studies have examined their significance in terms of clinical utility, i.e., biomarkers that inform prognostication and/or to predict therapeutic responses to be tested in future clinical trials. This review provides an overview of recent investigations into the relationship between molecular subtypes and the clinical management of patients with bladder cancer.
| S-EPMC7807369 | biostudies-literature
Project description:BackgroundN7-methylguanosine (m7G) is closely associated with tumor prognosis and immune response in many cancer types. The correlation between m7G and bladder cancer (BC) needs further study. We aimed to orchestrate molecular subtypes and identify key genes for BC from the perspective of m7G.MethodsRNA-seq and clinical data of BC patients were extracted from TCGA and GSE13507 datasets. The patients were subtyped by "ConsensusClusterPlus" and "limma." The clusters were validated by the Kaplan‒Meier curves, univariable and multivariate Cox regression models, the concordance index, and calibration curves. The immunotherapy response was evaluated by immune checkpoints, immune infiltration, TIDE score, and IMvigor210 cohort. Genomics of Drug Sensitivity in Cancer was utilized to predict the chemotherapy response between the clusters.ResultsThe m7G-related cluster was ultimately established by EIF4G1, NUDT11, NUDT10, and CCNB1. The independent prognostic value of the m7G-related cluster was validated by the TCGA and GSE13507 datasets. The cluster was involved in immune-associated pathways, such as neutrophil degranulation, antigen processing cross-presentation, and signaling by interleukins pathways. Meanwhile, cluster 2 was positively correlated with many immune checkpoints, such as CD274, CTLA4, HAVCR2, LAG3, PDCD1, and PDCD1LG2. The cluster 2 was significantly correlated with a higher TIDE score than the cluster 1. Furthermore, in the IMvigor210 cohort, patients in the cluster 1 had a higher response rate than those in the cluster 2. Patients in the cluster 2 were sensitive to many chemotherapies.ConclusionsWe successfully determined molecular subtypes and identified key genes for BC from the perspective of m7G, thereby providing a roadmap for the evolution of immunotherapy and precision medicine.
| S-EPMC9893617 | biostudies-literature
Project description:Background: Considering the heterogeneity and complexity of epigenetic regulation in bladder cancer, the underlying mechanisms of global DNA methylation modification in the immune microenvironment must be investigated to predict the prognosis outcomes and clinical response to immunotherapy. Methods: We systematically assessed the DNA methylation modes of 985 integrated bladder cancer samples with the unsupervised clustering algorithm. Subsequently, these DNA methylation modes were analyzed for their correlations with features of the immune microenvironment. The principal analysis algorithm was performed to calculate the DMRscores of each samples for qualification analysis. Findings: Three DNA methylation modes were revealed among 985 bladder cancer samples, and these modes are related to diverse clinical outcomes and several immune microenvironment phenotypes, e.g., immune-desert, immune-inflamed, and immune-excluded ones. Then patients were classified into high- and low-DMRscore subgroups according to the DMRscore, which was calculated based on the expression of DNA methylation related genes (DMRGs). Patients with the low-DMRscore subgroup presented a prominent survival advantage that was significantly correlated to the immune-inflamed phenotype. Further analysis revealed that patients with low DMRscores exhibited less TP53 wild mutation, lower cancer stage and molecular subtypes were mainly papillary subtypes. In addition, an independent immunotherapy cohort confirmed that DMRscore could serve as a signature to predict prognosis outcomes and immune responses. Conclusion: Global DNA methylation modes can be used to predict the immunophenotypes, aggressiveness, and immune responses of bladder cancer. DNA methylation status assessments will strengthen our insights into the features of the immune microenvironment and promote the development of more effective treatment strategies.
| S-EPMC8678484 | biostudies-literature
Project description:Bladder cancer (BLCA) is one of the most prevalent and heterogeneous urinary malignant tumors. Previous researches have reported a significant association between cancer-associated fibroblasts (CAFs) and poor prognosis of tumor patients. However, uncertainty surrounds the role of CAFs in the BLCA tumor microenvironment, necessitating further investigation into the CAFs-related gene signatures in BLCA. In this study, we identified three CAF subtypes in BLCA according to single-cell RNA-seq data and constructed CAFs-related risk score (CRRS) by screening 102,714 signatures. The survival analysis, ROC curves, and nomogram suggested that CRRS was a valuable predictor in 2,042 patients from 9 available public datasets and Xiangya real-world cohort. We further revealed the significant correlation between CRRS and clinicopathological characteristics, genome alterations, and epithelial-mesenchymal transition (EMT). A high CRRS indicated a non-inflamed phenotype and a lower remission rate of immunotherapy in BLCA. In conclusion, the CRRS had the potential to predict the prognosis and immunotherapy response of BLCA patients.
| S-EPMC10485638 | biostudies-literature
Project description:Objective: To develop and validate ubiquitination-related molecular subtypes and a novel prognostic index using ubiquitination-related genes (URGs) for patients with bladder cancer (BCa). Materials and Methods: We downloaded the clinical data and transcriptome data of BCa from TCGA and GEO database. Consensus clustering analysis was conducted to identify ubiquitination-related molecular subtypes for BCa. Besides, we performed univariate and multivariate Cox regression analysis to develop a novel prognostic URGs-related index for BCa. We conducted internal and external verification in TCGA cohort and GEO cohort, respectively. Furthermore, the associations of ubiquitination-related molecular subtypes and prognostic index with tumor immune environment were also investigated. Results: A total of four ubiquitination-related molecular subtypes of BCa were finally identified. These four molecular subtypes had significantly different clinical characteristics, prognosis, PD-L1 expression level and tumor microenvironment. Besides, we developed a novel prognostic index using six URGs (including HLA-A, TMEM129, UBE2D1, UBE2N, UBE2T and USP5). The difference in OS between high and low-risk group was statistically significant in training cohort, testing cohort, and validating cohort. The area under ROC curve (AUC) for OS prediction was 0.736, 0.723, and 0.683 in training cohort, testing cohort, and validating cohort, respectively. Multivariate survival analysis showed that this index was an independent predictor for OS. This prognostic index was especially suitable for subtype 1 and 3, older, male, high grade, AJCC stage III-IV, stage N0, stage T3-4 BCa patients. Conclusions: This study identified a total of four ubiquitination-related molecular subtypes with significantly different tumor microenvironment, prognosis, clinical characteristics and PD-L1 expression level. Besides, a novel ubiquitination-related prognostic index for BCa patients was developed and successfully verified, which performed well in predicting prognosis of BCa.
| S-EPMC8585742 | biostudies-literature
Project description:The recommended treatment for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. If progression to advanced disease occurs, then patients must undergo a radical cystectomy with risks of substantial morbidity and poor clinical outcome. Identifying tumors unlikely to respond to BCG can translate into alternative treatments, such as early radical cystectomy, targeted therapies, or immunotherapies. Here, we conducted molecular profiling of 132 patients with BCG-naive HR-NMIBC and 44 patients with recurrences after BCG (34 matched), which uncovered three distinct BCG response subtypes (BRS1, 2 and BRS3). Patients with BRS3 tumors had a reduced recurrence-free and progression-free survival compared with BRS1/2. BRS3 tumors expressed high epithelial-to-mesenchymal transition and basal markers and had an immunosuppressive profile, which was confirmed with spatial proteomics. Tumors that recurred after BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive patients with HR-NMIBC, and the molecular subtypes outperformed guideline-recommended risk stratification based on clinicopathological variables. For clinical application, we confirmed that a commercially approved assay was able to predict BRS3 tumors with an area under the curve of 0.87. These BCG response subtypes will allow for improved identification of patients with HR-NMIBC at the highest risk of progression and have the potential to be used to select more appropriate treatments for patients unlikely to respond to BCG.
| S-EPMC10572776 | biostudies-literature
Project description:Background: The efficiency of immune checkpoint inhibitors (ICIs) in bladder cancer (BLCA) treatment has been widely validated; however, the tumor response to ICIs was generally low. It is critical and urgent to find biomarkers that can predict tumor response to ICIs. The tumor microenvironment (TME), which may play important roles to either dampen or enhance immune responses, has been widely concerned. Methods: The cancer genome atlas BLCA (TCGA-BLCA) cohort (n = 400) was used in this study. Based on the proportions of 22 types of immune cells calculated by CIBERSORT, TME was classified by K-means Clustering and differentially expressed genes (DEGs) were determined. Based on DEGs, patients were classified into three groups, and cluster signature genes were identified after reducing redundant genes. Then TMEscore was calculated based on cluster signature genes, and the samples were classified to two subtypes. We performed somatic mutation and copy number variation analysis to identify the genetic characteristics of the two subtypes. Correlation analysis was performed to explore the correlation between TMEscore and the tumor response to ICIs as well as the prognosis of BLCA. Results: According to the proportions of immune cells, two TME clusters were determined, and 1,144 DEGs and 138 cluster signature genes were identified. Based on cluster signature genes, samples were classified into TMEscore-high (n = 199) and TMEscore-low (n = 201) subtypes. Survival analysis showed patients with TMEscore-high phenotype had better prognosis. Among the 45 differentially expressed micro-RNAs (miRNAs) and 1,033 differentially expressed messenger RNAs (mRNAs) between the two subtypes, 16 miRNAs and 287 mRNAs had statistically significant impact on the prognosis of BLCA. Furthermore, there were 94 genes with significant differences between the two subtypes, and they were enriched in RTK-RAS, NOTCH, WNT, Hippo, and PI3K pathways. The Tumor Immune Dysfunction and Exclusion (TIDE) score of TMEscore-high BLCA was statistically lower than that of TMEscore-low BLCA. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of TMEscore and tumor mutation burden (TMB) is 0.6918 and 0.5374, respectively. Conclusion: We developed a method to classify BLCA patients to two TME subtypes, TMEscore-high and TMEscore-low, and we found TMEscore-high subtype of BLCA had a good prognosis and a good response to ICIs.
| S-EPMC7957069 | biostudies-literature