Molecular classification of urothelial carcinoma: global mRNA classification versus tumour-cell phenotype classification.
TL;DR: It is suggested that a combination of molecular pathology (tumour‐cell phenotype) and global mRNA profiling (context) is required for adequate subtype classification of muscle‐invasive bladder cancer.
Abstract: Global mRNA expression analysis is efficient for phenotypic profiling of tumours, and has been used to define molecular subtypes for almost every major tumour type. A key limitation is that most tumours are communities of both tumour and non-tumour cells. This problem is particularly pertinent for analysis of advanced invasive tumours, which are known to induce major changes and responses in both the tumour and the surrounding tissue. To identify bladder cancer tumour-cell phenotypes and compare classification by tumour-cell phenotype with classification by global gene expression analysis, we analysed 307 advanced bladder cancers (cystectomized) both by genome gene expression analysis and by immunohistochemistry with antibodies for 28 proteins. According to systematic analysis of gene and protein expression data, focusing on key molecular processes, we describe five tumour-cell phenotypes of advanced urothelial carcinoma: urothelial-like, genomically unstable, basal/SCC-like, mesenchymal-like, and small-cell/neuroendocrine-like. We provide molecular pathological definitions for each subtype. Tumours expressing urothelial differentiation factors show inconsistent and abnormal protein expression of terminal differentiation markers, suggesting pseudo-differentiation. Cancers with different tumour-cell phenotypes may co-cluster (converge), and cases with identical tumour-cell phenotypes may cluster apart (diverge), in global mRNA analyses. This divergence/convergence suggests that broad global commonalities related to the invasive process may exist between muscle-invasive tumours regardless of specific tumour-cell phenotype. Hence, there is a systematic disagreement in subtype classification determined by global mRNA profiling and by immunohistochemical profiling at the tumour-cell level. We suggest that a combination of molecular pathology (tumour-cell phenotype) and global mRNA profiling (context) is required for adequate subtype classification of muscle-invasive bladder cancer. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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A. Gordon Robertson1, Jaegil Kim2, Hikmat Al-Ahmadie3, Joaquim Bellmunt4 +167 more•Institutions (16)
TL;DR: An analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms identified 5 expression subtypes that may stratify response to different treatments and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology.
1,638 citations
Cites methods or result from "Molecular classification of urothel..."
...The neuronal subtype was recently recognized by others in an independent cohort (Sjödahl et al., 2017)....
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...Included are two that we did not identify previously, neuronal and luminal, which have recently been corroborated in an independent cohort (Sjödahl et al., 2017)....
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PSL Research University1, Curie Institute2, Lund University3, BC Cancer Agency4, University of Bern5, University of North Carolina at Chapel Hill6, Federal University of Paraná7, Memorial Sloan Kettering Cancer Center8, Johns Hopkins University9, University Health Network10, University of Texas MD Anderson Cancer Center11, Brigham and Women's Hospital12, Queen Mary University of London13, Cedars-Sinai Medical Center14, University of British Columbia15, Aarhus University Hospital16, Baylor College of Medicine17, Broad Institute18
TL;DR: In this paper, a consensus set of six molecular classes (luminal papillary (24%), luminal nonspecified (8), luminal unstable (15), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%) was identified.
629 citations
TL;DR: Recent developments in the molecular and translational aspects of bladder cancer biology are examined and their current or potential future clinical applications in the management of bladdercancer are discussed.
Abstract: The field of research in bladder cancer has seen significant advances in recent years. Next-generation sequencing has identified the genes most mutated in bladder cancer. This wealth of information allowed the definition of driver mutations, and identification of actionable therapeutic targets, as well as a clearer picture of patient prognosis and therapeutic direction. In a similar vein, our understanding of the cellular aspects of bladder cancer has grown. The identification of the cellular geography and the populations of different cell types and quantifications of normal and abnormal cell types in tumours provide a better prediction of therapeutic response. Non-invasive methods of diagnosis, including liquid biopsies, have seen major advances as well. These methods will likely find considerable utility in assessing minimal residual disease following treatment and for early-stage diagnosis. A significant therapeutic impact on patients with bladder cancer is found in the use of immune checkpoint inhibitor therapeutics. These therapeutics have been shown to cure some patients with bladder cancer and significantly decrease adverse events. These developments provide patients with better monitoring opportunities, unique therapeutic options and greater hope for prolonged survival. This Review examines recent developments in the molecular and translational aspects of bladder cancer biology and discusses their current or potential future clinical applications in the management of bladder cancer.
247 citations
TL;DR: It is found that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment.
Abstract: Although substantial progress has been made in cancer biology and treatment, clinical outcomes of bladder carcinoma (BC) patients are still not satisfactory. The tumor microenvironment (TME) is a potential target. Here, by single-cell RNA sequencing on 8 BC tumor samples and 3 para tumor samples, we identify 19 different cell types in the BC microenvironment, indicating high intra-tumoral heterogeneity. We find that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment. We also find that monocytes undergo M2 polarization in the tumor region and differentiate. Furthermore, the LAMP3 + DC subgroup may be able to recruit regulatory T cells, potentially taking part in the formation of an immunosuppressive TME. Through correlation analysis using public datasets containing over 3000 BC samples, we identify a role for inflammatory cancer-associated fibroblasts (iCAFs) in tumor progression, which is significantly related to poor prognosis. Additionally, we characterize a regulatory network depending on iCAFs. These results could help elucidate the protumor mechanisms of iCAFs. Our results provide deep insight into cancer immunology and provide an essential resource for drug discovery in the future. Bladder urothelial carcinoma is one of the most prevalent urogenital cancer types with limited therapeutic options. Here, the authors characterize the tumor immune microenvironment of bladder cancer using single cell RNA sequencing and suggest a role for inflammatory cancer-associated fibroblasts in tumor progression.
204 citations
TL;DR: BLCA can be stratified into six molecular subtypes with different overall survival (OS) and molecular features, and molecular subtyping is a promising way to tailor disease management for those who will benefit most.
192 citations
References
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TL;DR: Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.
Abstract: The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.
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TL;DR: This paper proposed parametric and non-parametric empirical Bayes frameworks for adjusting data for batch effects that is robust to outliers in small sample sizes and performs comparable to existing methods for large samples.
Abstract: SUMMARY Non-biological experimental variation or “batch effects” are commonly observed across multiple batches of microarray experiments, often rendering the task of combining data from these batches difficult. The ability to combine microarray data sets is advantageous to researchers to increase statistical power to detect biological phenomena from studies where logistical considerations restrict sample size or in studies that require the sequential hybridization of arrays. In general, it is inappropriate to combine data sets without adjusting for batch effects. Methods have been proposed to filter batch effects from data, but these are often complicated and require large batch sizes (>25) to implement. Because the majority of microarray studies are conducted using much smaller sample sizes, existing methods are not sufficient. We propose parametric and non-parametric empirical Bayes frameworks for adjusting data for batch effects that is robust to outliers in small sample sizes and performs comparable to existing methods for large samples. We illustrate our methods using two example data sets and show that our methods are justifiable, easy to apply, and useful in practice. Software for our method is freely available at: http://biosun1.harvard.edu/complab/batch/.
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"Molecular classification of urothel..." refers methods in this paper
...Batch effects adjustments were performed with the COMBAT algorithm [15]....
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TL;DR: The landscape of gene expression across tissues is described, thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants are cataloged, complex network relationships are described, and signals from genome-wide association studies explained by eQTLs are identified.
Abstract: Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysi...
4,418 citations
TL;DR: Ch Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.
Abstract: Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsThis paper is distributed under the terms of the Creative Commons. Attribution-Non-Commercial-Share Alike license, and the online version of the paper is freely available to all readers.
2,257 citations
TL;DR: P53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53- like phenotype after therapy.
1,285 citations
"Molecular classification of urothel..." refers background in this paper
...Such a signature is the driving force behind both the UNC and the MDA classes termed ‘luminal’ [9,10]....
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...The MDA classification [9] also defines a luminal and a basal subtype, but introduces a third group, named TP53-like, distinguished by a TP53-related gene expression signature....
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