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This study suggests that deletion of p16 makes a critical contribution to progression of NMIBCs. Subsequent genome sequencing studies (such as reference 37) define a subgroup of MIBCs with this profile.
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This was the first major whole-exome sequencing study of bladder cancer, which identified frequent mutation of chromatin modifier genes.
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This is the most comprehensive analysis of MIBC so far, including whole-exome sequencing, RNA sequencing and profiling of microRNAs, methylation and protein expression. See also references 173 and 194.
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This study uses a genomic approach to bladder tumour subclassification. It describes potential subclasses of the 'gold-standard' stage and grade groups based on DNA copy number and mutation.
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This study was the first to identify oncogenic FGFR3 fusions in bladder cancer. Importantly, cell lines with FGFR3 fusions were those previously reported to show high sensitivity to FGFR-targeted agents.
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This study was the first to describe FGFR3 mutations in bladder cancer.
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This study describes widespread alterations in microRNA expression in bladder cancer. A particularly interesting finding in low-grade tumours is loss of miR-99a and miR-100, which leads to upregulation of FGFR3.
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Using the BBN-induced invasive bladder cancer mouse model, this study provides evidence for a tumour suppressor role for hedgehog signalling from urothelium to stroma that in turn influences urothelial cell differentiation. BMP4 and BMP5 were among the SHH-induced stromal factors that stimulated urothelial differentiation. Importantly, pharmacological activation of the BMP pathway was shown to block tumour progression in this system.
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This is a comprehensive review of the extensive literature on DNA hypermethylation in bladder cancer.
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This genome-wide methylation study of normal urothelium and tumours of all grades and stages found distinct patterns of hypomethylation in NMIBCs and widespread promoter hypermethylation in invasive tumours.
Lauss, M. et al. DNA methylation analyses of urothelial carcinoma reveal distinct epigenetic subtypes and an association between gene copy number and methylation status. Epigenetics 7, 858–867 (2012).
Hovestadt, V. et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510, 537–541 (2014).
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This study assesses combinations of urine biomarkers for detection and surveillance of bladder cancer in a large group of patients.
Zuiverloon, T. C. et al. Optimization of nonmuscle invasive bladder cancer recurrence detection using a urine based FGFR3 mutation assay. J. Urol. 186, 707–712 (2011).
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Kandimalla, R. et al. A 3-plex methylation assay combined with the FGFR3 mutation assay sensitively detects recurrent bladder cancer in voided urine. Clin. Cancer Res. 19, 4760–4769 (2013).
Allory, Y. et al. Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome. Eur. Urol. 65, 360–366 (2013).
This study identifies TERT promoter mutations at high frequency in bladder tumours of all grades and stages, and reports their use as a urine biomarker. These mutations are the most common event identified in bladder cancer so far.
Hurst, C. D., Platt, F. M. & Knowles, M. A. Comprehensive mutation analysis of the TERT promoter in bladder cancer and detection of mutations in voided urine. Eur. Urol. 65, 367–369 (2013).
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This study identifies tumour-initiating cells from bladder tumours of different grades and stages. A key finding is that tumour-initiating cells from aggressive tumours showed a basal phenotype, whereas those from non-invasive tumours had features of more differentiated cells, suggesting a non-basal derivation.
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This is one of three recent gene expression profiling studies of MIBC that define major basal and luminal expression subtypes. (See also references 37 and 194).
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This study was the first to describe a molecular taxonomy for bladder cancer based on gene expression profiling of tumours of all stages and grades. Molecular subtypes traversing pathological classification and with distinct clinical outcomes are reported.
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This is one of three recent gene expression profiling studies of MIBC that define major basal and luminal expression subtypes. See also references 37 and 173. This study defines two luminal subtypes, one of which contains tumours that show resistance to cisplatin-based therapy.
Choi, W. et al. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nature Rev. Urol. 11, 400–410 (2014).
This is a useful review of recent expression profiling studies that identifies overlap of clusters defined by different groups and highlights specific features of the subtypes defined.
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This excellent pan-cancer study includes data on MIBC from a TCGA study and shows alignment of bladder tumours with squamous features with aggressive breast and ovarian cancers.
Aine, M., Liedberg, F., Sjodahl, G. & Hoglund, M. Re: David J., McConkey, Woonyoung Choi, Colin, P. N. Dinney. New insights into subtypes of invasive bladder cancer: considerations of the clinician. Eur. Urol. http://dx.doi.org/10.1016/j.eururo.2014.08.063 (2014).
McConkey, D., Choi, W. & Dinney, C. Reply to Mattias Aine, Fredrik Liedberg, Gottfrid Sjodahl & Mattias Hoglund's Letter to the Editor re: David, J. McConkey, Woonyoung Choi, Colin, P. N. Dinney. New insights into subtypes of invasive bladder cancer: considerations of the clinician. Eur. Urol. http://dx.doi.org/10.1016/j.eururo.2014.08.064 (2014).
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