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Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling

Pure squamous cell carcinoma (SCC) is the most common pure variant form of bladder cancer, found in 2–5% of cases. It often presents late and is unresponsive to cisplatin‐based chemotherapy. The molecular features of these tumours have not been elucidated in detail. We carried out whole‐exome sequen...

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Autores principales: Hurst, Carolyn D, Cheng, Guo, Platt, Fiona M, Alder, Olivia, Black, Emma VI, Burns, Julie E, Brown, Joanne, Jain, Sunjay, Roulson, Jo‐An, Knowles, Margaret A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977277/
https://www.ncbi.nlm.nih.gov/pubmed/35289095
http://dx.doi.org/10.1002/cjp2.261
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author Hurst, Carolyn D
Cheng, Guo
Platt, Fiona M
Alder, Olivia
Black, Emma VI
Burns, Julie E
Brown, Joanne
Jain, Sunjay
Roulson, Jo‐An
Knowles, Margaret A
author_facet Hurst, Carolyn D
Cheng, Guo
Platt, Fiona M
Alder, Olivia
Black, Emma VI
Burns, Julie E
Brown, Joanne
Jain, Sunjay
Roulson, Jo‐An
Knowles, Margaret A
author_sort Hurst, Carolyn D
collection PubMed
description Pure squamous cell carcinoma (SCC) is the most common pure variant form of bladder cancer, found in 2–5% of cases. It often presents late and is unresponsive to cisplatin‐based chemotherapy. The molecular features of these tumours have not been elucidated in detail. We carried out whole‐exome sequencing (WES), copy number, and transcriptome analysis of bladder SCC. Muscle‐invasive bladder cancer (MIBC) samples with no evidence of squamous differentiation (non‐SD) were used for comparison. To assess commonality of features with urothelial carcinoma with SD, we examined data from SD samples in The Cancer Genome Atlas (TCGA) study of MIBC. TP53 was the most commonly mutated gene in SCC (64%) followed by FAT1 (45%). Copy number analysis revealed complex changes in SCC, many differing from those in samples with SD. Gain of 5p and 7p was the most common feature, and focal regions on 5p included OSMR and RICTOR. In addition to 9p deletions, we found some samples with focal gain of 9p24 containing CD274 (PD‐L1). Loss of 4q35 containing FAT1 was found in many samples such that all but one sample analysed by WES had FAT1 mutation or deletion. Expression features included upregulation of oncostatin M receptor (OSMR), metalloproteinases, metallothioneins, keratinisation genes, extracellular matrix components, inflammatory response genes, stem cell markers, and immune response modulators. Exploration of differentially expressed transcription factors identified BNC1 and TFAP2A, a gene repressed by PPARG, as the most upregulated factors. Known urothelial differentiation factors were downregulated along with 72 Kruppel‐associated (KRAB) domain‐containing zinc finger family protein (KZFP) genes. Novel therapies are urgently needed for these tumours. In addition to upregulated expression of EGFR, which has been suggested as a therapeutic target in basal/squamous bladder cancer, we identified expression signatures that indicate upregulated OSMR and YAP/TAZ signalling. Preclinical evaluation of the effects of inhibition of these pathways alone or in combination is merited.
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spelling pubmed-89772772022-04-05 Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling Hurst, Carolyn D Cheng, Guo Platt, Fiona M Alder, Olivia Black, Emma VI Burns, Julie E Brown, Joanne Jain, Sunjay Roulson, Jo‐An Knowles, Margaret A J Pathol Clin Res Original Articles Pure squamous cell carcinoma (SCC) is the most common pure variant form of bladder cancer, found in 2–5% of cases. It often presents late and is unresponsive to cisplatin‐based chemotherapy. The molecular features of these tumours have not been elucidated in detail. We carried out whole‐exome sequencing (WES), copy number, and transcriptome analysis of bladder SCC. Muscle‐invasive bladder cancer (MIBC) samples with no evidence of squamous differentiation (non‐SD) were used for comparison. To assess commonality of features with urothelial carcinoma with SD, we examined data from SD samples in The Cancer Genome Atlas (TCGA) study of MIBC. TP53 was the most commonly mutated gene in SCC (64%) followed by FAT1 (45%). Copy number analysis revealed complex changes in SCC, many differing from those in samples with SD. Gain of 5p and 7p was the most common feature, and focal regions on 5p included OSMR and RICTOR. In addition to 9p deletions, we found some samples with focal gain of 9p24 containing CD274 (PD‐L1). Loss of 4q35 containing FAT1 was found in many samples such that all but one sample analysed by WES had FAT1 mutation or deletion. Expression features included upregulation of oncostatin M receptor (OSMR), metalloproteinases, metallothioneins, keratinisation genes, extracellular matrix components, inflammatory response genes, stem cell markers, and immune response modulators. Exploration of differentially expressed transcription factors identified BNC1 and TFAP2A, a gene repressed by PPARG, as the most upregulated factors. Known urothelial differentiation factors were downregulated along with 72 Kruppel‐associated (KRAB) domain‐containing zinc finger family protein (KZFP) genes. Novel therapies are urgently needed for these tumours. In addition to upregulated expression of EGFR, which has been suggested as a therapeutic target in basal/squamous bladder cancer, we identified expression signatures that indicate upregulated OSMR and YAP/TAZ signalling. Preclinical evaluation of the effects of inhibition of these pathways alone or in combination is merited. John Wiley & Sons, Inc. 2022-03-14 /pmc/articles/PMC8977277/ /pubmed/35289095 http://dx.doi.org/10.1002/cjp2.261 Text en © 2022 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Hurst, Carolyn D
Cheng, Guo
Platt, Fiona M
Alder, Olivia
Black, Emma VI
Burns, Julie E
Brown, Joanne
Jain, Sunjay
Roulson, Jo‐An
Knowles, Margaret A
Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling
title Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling
title_full Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling
title_fullStr Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling
title_full_unstemmed Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling
title_short Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling
title_sort molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for osmr and yap signalling
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977277/
https://www.ncbi.nlm.nih.gov/pubmed/35289095
http://dx.doi.org/10.1002/cjp2.261
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