“Primary” and “secondary” muscle-invasive bladder cancer is more than just a surrogate for molecular subtypes
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ABSTRACT:
SUBMITTER: Pietzak E
PROVIDER: S-EPMC8798224 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Project description:Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease that often recurs despite aggressive treatment with neoadjuvant chemotherapy and (radical) cystectomy. Basal and luminal molecular subtypes have been identified that are linked to clinical characteristics and have differential sensitivities to chemotherapy. While it has been suggested that epigenetic mechanisms play a role in defining these subtypes, a thorough understanding of the biological mechanisms is lacking. This report details the first genome-wide analysis of histone methylation patterns of human primary bladder tumours by chromatin immunoprecipitations and next-generation sequencing (ChIP-seq). We profiled multiple histone marks: H3K27me3, a marker for repressed genes, and H3K4me1 and H3K4me3, which are indicators of active enhancers and active promoters. Integrated analysis of ChIP-seq data and RNA sequencing revealed that H3K4 mono-methylation demarcates MIBC subtypes, while no association was found for the other two histone modifications in relation to basal and luminal subtypes. Additionally, we identified differentially methylated H3K4me1 peaks in basal and luminal tumour samples, suggesting that active enhancers play a role in defining subtypes. Our study is the first analysis of histone modifications in primary bladder cancer tissue and provides an important resource for the bladder cancer community.
| S-EPMC7331601 | biostudies-literature
Project description:BackgroundHeterogeneity of muscle-invasive bladder cancer (MIBC) has been characterized using whole-genome mRNA expression data, showing distinct molecular and clinicopathological characteristics by subtypes. However, associations between risk factors and molecular subtypes have not been reported.MethodsFour previously published schemes were used to categorize molecular subtypes in 372 MIBC patients from the Cancer Genome Atlas (TCGA). Data on gene expression (RNA-seq), demographic, and clinicopathological characteristics were retrieved through TCGA data portal. Polytomous logistic regression was used to estimate the associations of subtypes by different schemes with age at diagnosis, obesity, and smoking.ResultsWhile some quantitative variation was evident, distinct molecular subtype schemes showed considerable consistency in the association with the risk factors. Generally, compared to patients with luminal-like tumors, patients with basal-like subtypes were more likely to be older (OR75 + yrs vs. <60 years range = 1.32-2.89), obese (ORobese vs. normal range = 1.30-3.05), and to start smoking at early age (OR<18 years vs. 25+ years range = 1.11-4.57).ConclusionsDifferent molecular subtypes of MIBC may have distinct risk profiles. Large population-based studies with detailed information on bladder cancer risk factors are needed to further define etiologic heterogeneity for bladder cancer.
| S-EPMC5477976 | biostudies-literature
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:Reliable factors predicting the disease course of non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) are unavailable. Molecular subtypes have potential for prognostic stratification of muscle-invasive bladder cancer, while their value for CIS patients is unknown. Here, the prognostic impact of both clinico-pathological parameters, including CIS focality, and immunohistochemistry-based surrogate subtypes was analyzed in a cohort of high-risk NMIBC patients with CIS. In 128 high-risk NMIBC patients with CIS, luminal (KRT20, GATA3, ERBB2) and basal (KRT5/6, KRT14) surrogate markers as well as p53 were analyzed in 213-231 biopsies. To study inter-lesional heterogeneity of CIS, marker expression in independent CIS biopsies from different bladder localizations was analyzed. Clinico-pathological parameters and surrogate subtypes were correlated with recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Forty-six and 30% of CIS patients exhibited a luminal-like (KRT20-positive, KRT5/6-negative) and a null phenotype (KRT20-negative, KRT5/6-negative), respectively. A basal-like subtype (KRT20-negative, KRT5/6-positive) was not observed. A significant degree of inter-lesional CIS heterogeneity was noted, reflected by 23% of patients showing a mixed subtype. Neither CIS surrogate subtype nor CIS focality was associated with patient outcome. Patient age and smoking status were the only potentially independent prognostic factors predicting RFS, PFS, OS, and PFS, respectively. In conclusion, further clarification of heterogeneity of surrogate subtypes in HR NMIBC and their prognostic value is of importance with regard to potential implementation of molecular subtyping into clinical routine. The potential prognostic usefulness of patient age and smoking status for high-risk NMIBC patients with CIS needs further validation.
| S-EPMC8364543 | biostudies-literature
Project description:It remains unclear how to implement the recently revealed basal and luminal subtypes of muscle-invasive bladder cancer (MIBC) into daily clinical routine and whether molecular marker panels can be reduced. The mRNA expression of basal (KRT5) and luminal (FOXA1, GATA3, KRT20) markers was measured by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and correlated to clinicopathological features, recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS) in 80 patients with MIBC who underwent radical cystectomy. Additionally, the correlation of single markers with the basal and non-basal subtypes defined by a 36-gene panel was examined and then validated in the TCGA (The Cancer Genome Atlas) cohort. High expression of FOXA1 (p = 0.0048) and KRT20 (p = 0.0317) was associated with reduced RFS. In the multivariable analysis, only FOXA1 remained an independent prognostic marker for DFS (p = 0.0333) and RFS (p = 0.0310). FOXA1 expression (AUC = 0.79; p = 0.0007) was closest to the combined marker expression (AUC = 0.79; p = 0.0015) in resembling the non-basal subtype defined by the 36-gene panel. FOXA1 in combination with KRT5 may be used to distinguish the basal and non-basal subtypes of MIBC.
| S-EPMC7230662 | biostudies-literature
Project description:The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
| S-EPMC8052448 | biostudies-literature
Project description:BackgroundWe sought to determine whether differences in subtype distribution and differentially expressed genes exist between African Americans (AAs) and European Americans (EAs) in patients with high-risk nonmuscle-invasive bladder cancer (NMIBC).MethodsWe performed a retrospective cohort study including 26 patients (14 AAs and 12 EAs) from the University of Texas Medical Branch and the Durham Veterans Affair Health Care System from 2010 to 2020 among treatment naïve, high-risk NMIBC. Profiled gene expressions were performed using the UROMOL classification system.ResultsUROMOL racial subtype distributions were similar with class 2a being most common with 10 genes commonly upregulated in AAs compared to EAs including EFEMP1, S100A16, and MCL1 which are associated with progression to muscle-invasive bladder cancer, mitomycin C resistance, and bacillus Calmette-Guérin durability, respectively. We used single nuclei analysis to map the malignant cell heterogeneity in urothelial cancer which 5 distinct malignant epithelial subtypes whose presence has been associated with different therapeutic response prediction abilities. We mapped the expression of the 10 genes commonly upregulated by race as a function of the 5 malignant subtypes. This showed borderline (P = 0.056) difference among the subtypes suggesting AAs and EAs may be expected to have different therapeutic responses to treatments for bladder cancer. AAs were enriched with immune-related, inflammatory, and cellular regulation pathways compared to EAs, yet appeared to have reduced levels of the aggressive C3/CDH12 bladder tumor cell population.ConclusionsWhile premature, gene expression differed between AAs and EAs, supporting potential race-based etiologies for muscle-invasion, response to treatments, and transcriptome pathway regulations.
| S-EPMC9741768 | 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:Conflicting results of survival outcomes for primary and secondary muscle-invasive bladder cancer (MIBC) have been reported in previous studies. Primary MIBC is defined as presentation of muscle-invasive disease at initial diagnosis while secondary MIBC presumes that non-muscle invasive disease later progressed to MIBC. Due to the varying reports, we conducted a systematic review and meta-analysis to compare survival outcomes between the two groups. Relevant studies were retrieved from Medline, Embase, the Cochrane Library, and Scopus using a comprehensive search approach. Cancer-specific survival (CSS) was the outcome measure. A total of 14 studies involving 4,075 cases were included. Patients with secondary MIBC were significantly correlated with worse CSS in model I (pooled HR: 1.29, 95% CI: 1.07-1.56, P = 0.008). The results of sensitivity analyses indicated that the omission of any single study each time did not have a significant impact on the combined risk estimates. Egger's test suggested no publication bias among these studies. The European Organization for Research and Treatment of Cancer (EORTC) risk score offers the possibility of stratifying the secondary MIBC patients into different risk groups. In high-risk NMIBC, timely radical cystectomy should be considered. Further study is required to assess the multimodal therapy in both high-risk NMIBC and secondary MIBC patients as well as to evaluate genetic and molecular drivers of tumor induction, promotion, and progression.
| S-EPMC5954122 | biostudies-literature
Project description:We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
| S-EPMC5687509 | biostudies-literature