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Update on bladder cancer molecular subtypes.

ABSTRACT: 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.

SUBMITTER: Fong MHY

PROVIDER: S-EPMC7807369 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Update on bladder cancer molecular subtypes.

Fong Megan Hoi Yan MHY Feng Mingxiao M McConkey David J DJ Choi Woonyoung W

Translational andrology and urology 20201201 6

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), a ...[more]

PMID: 33457262

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Project description:The emergence of immunotherapy has provided an option of treatment methods for bladder cancer (BC). However, the beneficiaries of immunotherapy are still limited to small-scale patients, and immunotherapy-related adverse events often occur. It is a major challenge for clinical work to study the immune subtypes of BC and the molecular mechanism of immune escape, and identify the immune responders accurately. Here, we explore the immune molecular subtypes of bladder cancer and potential escape mechanisms. First, we screened the expression profiles of 303 differentially expressed immune-related genes in BC patients from the Cancer Genome Atlas (TCGA) database, and successfully identified 4 molecular subtypes of BC. By comparing the clinical characteristics, immune cells infiltration, the expression of checkpoint genes, human leukocyte antigen (HLA) genes, and gene mutation status of different subtypes, we identified different clinical and immunological characteristics of 4 subtypes. Among 4 subtypes, Cluster 2 met the general characteristics of immunotherapy responders and responded well to immunotherapy, while Cluster 4 had the highest expression of immune characteristics, and is similar to the immune environment of normal bladder tissue. Then, the weighted gene co-expression network analysis (WGCNA) of immune-related genes revealed that brown module was positively correlated with subtypes. Pathway enrichment analysis explored the major pathways associated with subtypes, which are also associated with immune escape mechanisms. Moreover, the decision tree model, which was constructed by the principle of random forest screening factors, was also validated in internal validation set and external validation set from the Gene Expression Omnibus (GEO) cohort (GSE133624), and could achieve accurate subtypes prediction for BC patients with high-throughput sequencing. Taken together, we explored the immune molecular subtypes and their mechanisms of BC, and these results may provide guidance for the development of new BC immunotherapy strategies.

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.

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Update on bladder cancer molecular subtypes.

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Update on bladder cancer molecular subtypes.

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