Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE124305 | GEO | 2019/01/01
REPOSITORIES: GEO
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Project description:For patients with muscle-invasive bladder cancer, there are no biomarkers in clinical use that can identify patients that are sensitive or resistant to neoadjuvant chemotherapy. This study investigates how molecular subtypes impact pathological response and survival in 149 patients receiving preoperative cis-platin based chemotherapy by tumor classification using transcriptomic profiling and a 13-marker immunostaining panel. Furthermore, we explored to what extent gene expression signatures can predict chemotherapy response beyond molecular subtypes. We observed improved pathological response rates and survival outcomes for patients presenting with genomically unstable (GU) and urothelial-like (Uro) subtypes compared to the basal-squamous (BASQ) subtype following neoadjuvant chemotherapy and radical cystectomy. Also, SPP1, coding for osteopontin, displayed a clear subtype-dependent effect on chemotherapy response, confirmed at the protein level. Based on our findings, we hypothesize that urothelial cancer of the luminal-like GU- and Uro-subtypes are more responsive to cisplatin-based chemotherapy which may influence patient selection pending further research.
2021-11-19 | GSE169455 | GEO
Project description:Radical cystectomy with preoperative cisplatin-based neoadjuvant chemotherapy (NAC) is a current standard care for muscle-invasive bladder cancers (MIBCs). However, the response rate remains relatively low, and current clinico-pathologic and molecular classifications are inadequate to prospectively stratify MBIC patients regarding the NAC response. Here, we showed that dysregulation in glutathione (GSH) pathway is fundamental for the NAC resistance of MBICs. Comprehensive analysis of transcriptome profiles from four independent cohorts revealed that GSH metabolism and immune response genes were significantly enriched in NAC resistant and sensitive MIBC tumors, respectively. A machine learning based tumor/stroma classifier was applied for high-throughput digitalized immunohistochemistry analysis, identifying GSH dynamic proteins including glutaminase-1 (GLS1) were associated with the NAC resistance and unfavorable clinical characteristics. Consistently, GSH dynamics was activated in cisplatin resistant human MIBC cells, stimulating their proliferation, stemness features, and invasion. Combination treatment of GSH dynamics modulators and cisplatin significantly suppressed tumor growth in an orthotopic xenograft animal model. Our results demonstrate the prognostic and therapeutic values of GSH dynamic mediators in determining the clinical features and response to NAC of patients with MIBCs.
2023-08-21 | GSE212810 | GEO
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
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:Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARg are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3 and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remains unknown. Result: We determine the genome-wide transcriptome, enhancer landscape and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. Conclusion: In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.
2021-01-04 | GSE148079 | GEO
Project description:Stage T1 bladder cancers have the highest progression and recurrence rates of all non-muscle invasive bladder tumors. T1 tumors are heterogeneous; while most T1 patients are treated with BCG, many will progress and die from bladder cancer, and particularly aggressive tumors could be treated by early cystectomy. To better understand the molecular heterogeneity of T1 cancers, we performed transcriptome profiling and unsupervised clustering, identifying five consensus subtypes of T1 tumors treated with reTUR, induction and maintenance BCG. The T1-LumGU subtype was associated with CIS (6/13, 46% of all CIS), had high E2F1 and EZH2 expression, and enriched E2F target and G2M checkpoint Hallmarks. T1-Inflam was inflamed and infiltrated with immune cells. While most T1 tumors were classified as luminal papillary, the T1-TLum subtype had the highest median Luminal Papillary score and FGFR3 expression, no recurrence events, and the fewest copy number gains. T1-Myc and T1-Early subtypes had the most recurrences (14/30 within 24 months), highest median MYC expression, and, when combined, had significantly worse recurrence-free survival than the other three subtypes. T1-Early had 5 (38%) recurrences within the first 6 months of BCG, and repressed IFN-alpha and IFN-gamma Hallmarks and inflammation. We developed a single-patient T1 classifier and validated our subtype biology in a second cohort of T1 tumors. Future research will be necessary to validate the proposed T1 subtypes and to determine if therapies can be individualized for each subtype.
2020-07-13 | GSE154261 | GEO
Project description:Muscle invasive bladder cancer (MIBC) is a heterogeneous disease with a high recurrence rate and poor clinical outcomes. Molecular subtype provides a new framework for the study of MIBC heterogeneity. Clinically, MIBC can be classified as basal and luminal subtypes, they display different clinical and pathological characteristics, but the molecular mechanism is still unclear. Lipidomic and metabolomic molecules have recently been considered to play an important role in the genesis and development of tumors, especially as potential biomarkers. Their different expression profiles in basal and luminal subtypes provide clues for the molecular mechanism of basal and luminal subtypes and the discovery of new biomarkers. Herein, we stratified MIBC patients into basal and luminal subtype using a MIBC classifier based on transcriptome expression profiles. We qualitatively and quantitatively analyzed the lipids and metabolites of basal and luminal MIBC subtypes, and identified differential lipid and metabolite profiles of them. Our results suggest that free fatty acids (FFA) and sulfatides (SL), which are closely associated with immune and stromal cell types, can contribute to the diagnosis of basal and luminal subtypes of MIBC. Moreover, we showe that glycerophosphocholine (GCP)/imidazoles and nucleosides/imidazoles ratios can accurately distinguish the basal and luminal tumors. Overall, by integrating transcriptomic, lipidomic, and metabolomic data, our study reveals specific biomarkers to differentially diagnose basal and luminal MIBC subtypes and may provide a basis for precision therapy of MIBC.
2021-07-08 | GSE179440 | GEO
Project description:Identifying patients that benefit from cisplatin-based adjuvant chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC). The purpose of this study is to correlate “luminal” and “basal” type protein expression with histological subtypes, to investigate the prognostic impact on survival after adjuvant chemotherapy and to define molecular subtypes of “double negative” patients (i.e. without expression of CK5/6 or GATA3).
2022-05-14 | GSE198607 | GEO
Project description:A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 invasive breast tumors from the Carolina Breast Cancer Study (CBCS), a population-based study of invasive breast cancer. Concensus clustering using methylation (β) values for the 167 most variant CpG loci defined 4 clusters differing most distinctly in hormone receptor (HR) status, intrinsic subtype (luminal versus basal-like) and p53 mutation status. Supervised analyses for HR status, subtype, and p53 status identified differentially methylated CpG loci with considerable overlap (n=266). Concensus clustering also defined a hypermethylated luminal-enriched tumor cluster 3; gene ontology analysis of cluster 3 hypermethylated loci revealed enrichment for developmental genes, including homeobox domain genes (HOXB13, PAX6, IPF1, EYA4, DLK1, IHH, ISL1, TBX1, SOX1, SOX17). The hypermethylated luminal-enriched cluster 3 independently predicted poorer survival in multivariate Cox proportional hazard analysis, and this finding was confirmed in analysis of luminal A tumors. This study demonstrates epigenetic heterogeneity among breast tumors of a single intrinsic subtype, and shows that epigenetic patterns are strongly associated with HR status, subtype, and p53 mutation status. Among HR+ tumors, a gene signature characterized by hypermethylation of developmental genes may have prognostic value. Genes differentially methylated between clinically-important tumor subsets have roles in differentiation, development, and tumor growth and may be critical to inducing and maintaining tumor phenotypes and clinical outcomes. 517 breast tumors, 9 normal breast tissues
2015-04-07 | E-GEOD-51557 | biostudies-arrayexpress
Project description:A Cartes dM-^RIdentite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net/). Seven transcriptome datasets corresponding to a new series of 85 MIBC (Muscle-invasive bladder cancer) and six publicly-available series (298 MIBC) were analyzed. Tumors were classified by consensus clustering. Overall survival was determined from Kaplan-Meier curves. The role of the EGFR pathway was investigated by pathway bioinformatics analysis, determination of the expression levels of its components (by microarray, RT-qPCR and western blot) and of EGFR copy number by CGH arrays. A 40-gene transcriptomic classifier was used to identify basal-like cell lines and a basal-like mouse model. Please note M-^QMIBC molecular subtype': tumors classification using consensus clustering.
2014-06-01 | E-MTAB-1803 | biostudies-arrayexpress