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The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data fr...

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Autores principales: Inman, Gareth J., Wang, Jun, Nagano, Ai, Alexandrov, Ludmil B., Purdie, Karin J., Taylor, Richard G., Sherwood, Victoria, Thomson, Jason, Hogan, Sarah, Spender, Lindsay C., South, Andrew P., Stratton, Michael, Chelala, Claude, Harwood, Catherine A., Proby, Charlotte M., Leigh, Irene M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131170/
https://www.ncbi.nlm.nih.gov/pubmed/30202019
http://dx.doi.org/10.1038/s41467-018-06027-1
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author Inman, Gareth J.
Wang, Jun
Nagano, Ai
Alexandrov, Ludmil B.
Purdie, Karin J.
Taylor, Richard G.
Sherwood, Victoria
Thomson, Jason
Hogan, Sarah
Spender, Lindsay C.
South, Andrew P.
Stratton, Michael
Chelala, Claude
Harwood, Catherine A.
Proby, Charlotte M.
Leigh, Irene M.
author_facet Inman, Gareth J.
Wang, Jun
Nagano, Ai
Alexandrov, Ludmil B.
Purdie, Karin J.
Taylor, Richard G.
Sherwood, Victoria
Thomson, Jason
Hogan, Sarah
Spender, Lindsay C.
South, Andrew P.
Stratton, Michael
Chelala, Claude
Harwood, Catherine A.
Proby, Charlotte M.
Leigh, Irene M.
author_sort Inman, Gareth J.
collection PubMed
description Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterisation of a panel of 15 cSCC tumour-derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a valuable resource for the validation of tumour drivers and therapeutic targets.
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spelling pubmed-61311702018-09-12 The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature Inman, Gareth J. Wang, Jun Nagano, Ai Alexandrov, Ludmil B. Purdie, Karin J. Taylor, Richard G. Sherwood, Victoria Thomson, Jason Hogan, Sarah Spender, Lindsay C. South, Andrew P. Stratton, Michael Chelala, Claude Harwood, Catherine A. Proby, Charlotte M. Leigh, Irene M. Nat Commun Article Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterisation of a panel of 15 cSCC tumour-derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a valuable resource for the validation of tumour drivers and therapeutic targets. Nature Publishing Group UK 2018-09-10 /pmc/articles/PMC6131170/ /pubmed/30202019 http://dx.doi.org/10.1038/s41467-018-06027-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Inman, Gareth J.
Wang, Jun
Nagano, Ai
Alexandrov, Ludmil B.
Purdie, Karin J.
Taylor, Richard G.
Sherwood, Victoria
Thomson, Jason
Hogan, Sarah
Spender, Lindsay C.
South, Andrew P.
Stratton, Michael
Chelala, Claude
Harwood, Catherine A.
Proby, Charlotte M.
Leigh, Irene M.
The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature
title The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature
title_full The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature
title_fullStr The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature
title_full_unstemmed The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature
title_short The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature
title_sort genomic landscape of cutaneous scc reveals drivers and a novel azathioprine associated mutational signature
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131170/
https://www.ncbi.nlm.nih.gov/pubmed/30202019
http://dx.doi.org/10.1038/s41467-018-06027-1
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