Molecular subtyping of “double negative” MIBC
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE198607 | GEO | 2022/05/14
REPOSITORIES: GEO
Similar Datasets
Project description:Molecular subtyping of “double negative” MIBC
| PRJNA816119 | ENA
Project description:Four different molecular classifications of muscle-invasive bladder cancer (MIBC) based on gene expression have been proposed. With the ultimate goal of utilizing these molecular subtypes for personalized treatment, we investigated their significance in the context of neoadjuvant cisplatin-based chemotherapy (NAC).
2017-05-25 | GSE87304 | GEO
Project description:Analyses of large transcriptomics datasets of muscle-invasive bladder cancer (MIBC) has led to a consensus classification. Molecular subtypes of upper tract urothelial carcinomas (UTUC) are less known. Our objective was to determine the relevance of consensus classification in UTUCs by characterizing a novel cohort of surgically treated ≥pT1 tumors.Subtype IHC markers GATA3-CK5/6-TUBB2B in multiplex, CK20, p16 and Ki67, MMR proteins, PD-L1 IHC were evaluated. Heterogeneity was assessed morphologically and/or with subtype IHC. FGFR3 mutations were identified by pyrosequencing. We performed 3’RNA-seq, including with multisampling in heterogeneous cases. Consensus classes, unsupervised groups, and microenvironment cell abundance were determined using gene expression.Most of the 66 patients were men (77.3%), with pT1 (n=23, 34.8%) or pT2-4 stage UTUC (n=43, 65.2%). FGFR3 mutations and dMMR status were identified in 40% and 4.7% of cases, respectively. Consensus subtypes robustly classified UTUCs and reflected intrinsic subgroups. All pT1 tumors were classified as Luminal papillary (LumP). Combining our consensus classification results to that of previously published UTUC cohorts, LumP tumors represented 57.2% of ≥pT2 UTUC, which was significantly higher than in MIBC. Ten patients (15.2%) harbored areas of distinct subtypes. Consensus classes were associated with FGFR3 mutations, stage, morphology and IHC. The majority of LumP tumors were characterized by low immune infiltration and PD-L1 expression, in particular if FGFR3 mutated.
2023-10-10 | GSE244957 | GEO
Project description:Muscle invasive bladder cancer (MIBC) is one of the aggressive cancer with limited treatment options. Targeted gene expression profiling in normal and tumor samples from MIBC patients could aid in identification of potential therapeutic targets. Thus we used kinase specific panel to study their expression pattern and to identify targetable genes.
2020-04-20 | GSE130598 | GEO
Project description:Triple-negative (TN) breast cancers need to be refined in order to identify therapeutic subgroups of patients. We conducted an unsupervised analysis of microarray gene-expression profiles of 107 TN breast cancer patients and undertook robust functional annotation of the molecular entities found by means of numerous approaches including immunohistochemistry and gene-expression signatures. An 87 TN external cohort was used for validation. Fuzzy clustering separated TN tumours into three clusters: C1 (22.4%), C2 (44.9%) and C3 (32.7%). C1 patients were older (mean = 64.6 years) than C2 (mean = 56.8 years; P = 0.03) and C3 patients (mean = 51.9 years; P = 0.0004). Histological grade and Nottingham prognostic index were higher in C2 and C3 than in C1 (P < 0.0001 for both comparisons). Significant event-free survival (EFS) (P = 0.03) was found according to cluster membership: patients belonging to C3 had a better outcome than patients in C1 (P = 0.01) and C2 (P = 0.02). EFS analysis results were confirmed when our cohort was pooled with external cohort (n = 194; P = 0.01). Functional annotation showed that 22% of TN patients were not basal-like (C1). C1 was enriched in luminal subtypes and positive androgen receptor (luminal androgen receptor [LAR]). C2 could be considered as an almost pure basal-like cluster. C3, enriched in basal-like subtypes, but to a lesser extent, included 26% of claudin-low subtypes. Dissection of immune response showed that high immune response (HIR) and low M2-like macrophages were a hallmark of C3, and that these patients had a better EFS than C2 patients, characterized by low immune response (LIR) and high M2-like macrophages: P = 0.02 for our cohort, and P = 0.03 for pooled cohorts. We identified 3 subtypes of TN patients: LAR (22%), basal-like with LIR and high M2-like macrophages (45%) and basal-enriched with HIR and low M2-like macrophages (33%). We pointed out that macrophages and other immune effectors offer a variety of therapeutic targets in breast cancer, and particularly in TN basal-like tumours. Furthermore, we showed that CK5 antibody was better suited than CK5/6 antibody to subtype TN patients. Subtyping molecular characterization within a cohort of 107 TN-IHC by means of gene expression profiling
2015-05-19 | E-GEOD-58812 | biostudies-arrayexpress
Project description:Background: The response to neoadjuvant cisplatin-based chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) is impaired in up to 50% of patients due to chemoresistance, with no predictive biomarkers in clinical use. RNA-binding motif protein 3 (RBM3) has emerged as a putative modulator of chemotherapy response but has a hitherto unrecognized role in MIBC. Methods: Tumour-specific RBM3 protein expression was assessed via immunohistochemistry in paired transurethral resection of the bladder (TURB) specimens, cystectomy specimens and lymph node metastases from 145 patients. The effect of RBM3 suppression on chemosensitivity was examined in RT4 and T24 cells in vitro. RNA-sequencing was applied to compare gene expression profiles between siRBM3-treated and control cells. Findings: RBM3 protein expression was significantly higher in TURB compared to cystectomy specimens but showed consistency between primary tumours and lymph node metastases. High tumour-specific RBM3 expression was significantly associated with a reduced risk of recurrence in NAC treated patients. In T24 cells, which displayed higher RBM3 levels than RT4 cells, RBM3 silencing conferred a decreased sensitivity to cisplatin and gemcitabine. RNA-sequencing revealed potential involvement of RBM3 in facilitating cell cycle progression, in particular G1/S-phase transition, and initiation of DNA replication. Interpretation: The presented data highlight the predictive value of RBM3 in MIBC, which could, if prospectively validated, improve treatment stratification of patients with this aggressive disease.
2022-01-11 | GSE167558 | GEO
Project description:Triple-negative (TN) breast cancers need to be refined in order to identify therapeutic subgroups of patients. We conducted an unsupervised analysis of microarray gene-expression profiles of 107 TN breast cancer patients and undertook robust functional annotation of the molecular entities found by means of numerous approaches including immunohistochemistry and gene-expression signatures. An 87 TN external cohort was used for validation. Fuzzy clustering separated TN tumours into three clusters: C1 (22.4%), C2 (44.9%) and C3 (32.7%). C1 patients were older (mean = 64.6 years) than C2 (mean = 56.8 years; P = 0.03) and C3 patients (mean = 51.9 years; P = 0.0004). Histological grade and Nottingham prognostic index were higher in C2 and C3 than in C1 (P < 0.0001 for both comparisons). Significant event-free survival (EFS) (P = 0.03) was found according to cluster membership: patients belonging to C3 had a better outcome than patients in C1 (P = 0.01) and C2 (P = 0.02). EFS analysis results were confirmed when our cohort was pooled with external cohort (n = 194; P = 0.01). Functional annotation showed that 22% of TN patients were not basal-like (C1). C1 was enriched in luminal subtypes and positive androgen receptor (luminal androgen receptor [LAR]). C2 could be considered as an almost pure basal-like cluster. C3, enriched in basal-like subtypes, but to a lesser extent, included 26% of claudin-low subtypes. Dissection of immune response showed that high immune response (HIR) and low M2-like macrophages were a hallmark of C3, and that these patients had a better EFS than C2 patients, characterized by low immune response (LIR) and high M2-like macrophages: P = 0.02 for our cohort, and P = 0.03 for pooled cohorts. We identified 3 subtypes of TN patients: LAR (22%), basal-like with LIR and high M2-like macrophages (45%) and basal-enriched with HIR and low M2-like macrophages (33%). We pointed out that macrophages and other immune effectors offer a variety of therapeutic targets in breast cancer, and particularly in TN basal-like tumours. Furthermore, we showed that CK5 antibody was better suited than CK5/6 antibody to subtype TN patients.
2015-05-19 | GSE58812 | GEO
Project description:High mortality rate of muscle-invasive bladder cancer (MIBC) and complexity of disease demand new multi-targeting treatment strategies. Targeting proliferating cell nuclear antigen (PCNA) with a peptide containing the AlkB homologue 2 PCNA interacting motif (APIM), is shown to impair multiple vital cellular stress responses and induce hypersensitivity against several chemotherapeutics in different pre-clinical models. This study examine the anti-cancer efficacy of the novel APIM-peptide drug when combined with cisplatin-based therapies (cisplatin, cisplatin/gemcitabine (GC) and methotrexate/vinblastine/adriamycin/cisplatin (MVAC)) in a panel of bladder cancer (BC) cells and with intravenous cisplatin-therapy in a rat MIBC-model. Furthermore, we explore the molecular mechanisms underlying the observed effects on a genomic, proteomic and metabolomic level using microarray, multiplexed inhibitor bead (MIB)-assay, and targeted mass spectrometric metabolite profiling. The APIM-peptide significantly increased the efficacy of all cisplatin-based therapies in all BC cell lines tested, including a cisplatin resistant cell line and reduced the tumor load in cisplatin treated MIBC-bearing rats. Genome and proteome analysis of APIM-peptide/cisplatin treated BC cells revealed reduced expression of multiple proteins frequently overexpressed in MIBC. Of notice, the EGFR/ERBB2, PI3K/Akt and MAPK signaling pathways and anti-apoptosis were downregulated. We suggest that the anti-cancer effect of the APIM-peptide is through the downregulation of several known oncogenic signaling pathways including anti-apoptosis. Together our results indicate that the APIM-peptide represents a potential improved treatment approach for patients with MIBC.
2018-09-10 | PXD008724 | Pride
Project description:Oesophageal cancer is the ninth most common cancer in the UK and accounts for 5% of all cancer deaths. The incidence of the disease in men has risen 50% in the last 25 years with the commonest pathological subtype in the West being adenocarcinoma, while in East Asia oesophageal squamous cell carcinoma predominates. Despite efforts to screen for Barrett’s oesophagus, and pre-operatively select OAC patients who are likely to benefit from potentially curative surgery, survival remains poor. The five year survival rate is less than 17% and even in early stage locoregional confined disease this figure lies between 25-35%. A significant improvement in overall survival has been demonstrated with neo-adjuvant or peri-operative chemotherapy but the optimal approach for individual patients remains unclear. A consistent finding has been that complete histopathological response to neo-adjuvant chemotherapy is a prognostic biomarker for increased survival benefit. Therefore, there is a pressing need to identify biomarkers capable of predicting response, enabling clinicians to select patients for whom neo-adjuvant therapies would be beneficial. This experiment represents gene expression profiling of 60 pre-treatment formalin-fixed paraffin embedded (FFPE) oesophageal adenocarcinoma biopsies. All patients were treated with neo-adjuvant cisplatin-based chemotherapy prior to surgical resection at the Northern Ireland Cancer Centre from 2004-2012. The aim of the experiment was to carry out functional enrichment of pathological responders and non-responders to neo-adjuvant chemotherapy in order to identify novel mechanism of drug resistance or chemo-sensitivity.
2018-05-10 | E-MTAB-4666 | biostudies-arrayexpress
Project description:Background and Objective: Neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression. Material and Methods: From 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method. Results: LASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02). Conclusions: We have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing.
2023-06-20 | GSE235067 | GEO