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

Gareth J. Inman; Jun Wang; Ai Nagano; Ludmil B. Alexandrov; Karin J. Purdie; Richard G. Taylor; Victoria Sherwood; Jason Thomson; Sarah Hogan; Lindsay C. Spender; Andrew P. South; Michael Stratton; Claude Chelala; Catherine A. Harwood; Charlotte M. Proby; Irene M. Leigh

doi:10.1038/s41467-018-06027-1

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

Gareth J. Inman (Lead / Corresponding author), Jun Wang (Lead / Corresponding author), Ai Nagano, Ludmil B. Alexandrov, Karin J. Purdie, Richard G. Taylor, Victoria Sherwood, Jason Thomson, Sarah Hogan, Lindsay C. Spender, Andrew P. South, Michael Stratton, Claude Chelala, Catherine A. Harwood, Charlotte M. Proby, Irene M. Leigh (Lead / Corresponding author)

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Abstract

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.

Original language	English
Article number	3667
Pages (from-to)	1-14
Number of pages	14
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06027-1
Publication status	Published - 10 Sept 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Final published version, 2.28 MBLicence: CC BY

Proby, Charlotte
- Cancer Research - Professor (Research Only) of Dermatology
Person: Academic

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Inman, G. J., Wang, J., Nagano, A., Alexandrov, L. B., Purdie, K. J., Taylor, R. G., Sherwood, V., Thomson, J., Hogan, S., Spender, L. C., South, A. P., Stratton, M., Chelala, C., Harwood, C. A., Proby, C. M., & Leigh, I. M. (2018). The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. Nature Communications, 9(1), 1-14. Article 3667. https://doi.org/10.1038/s41467-018-06027-1

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title = "The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature",

abstract = "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.",

author = "Inman, {Gareth J.} and Jun Wang and Ai Nagano and Alexandrov, {Ludmil B.} and Purdie, {Karin J.} and Taylor, {Richard G.} and Victoria Sherwood and Jason Thomson and Sarah Hogan and Spender, {Lindsay C.} and South, {Andrew P.} and Michael Stratton and Claude Chelala and Harwood, {Catherine A.} and Proby, {Charlotte M.} and Leigh, {Irene M.}",

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Inman, GJ, Wang, J, Nagano, A, Alexandrov, LB, Purdie, KJ, Taylor, RG, Sherwood, V, Thomson, J, Hogan, S, Spender, LC, South, AP, Stratton, M, Chelala, C, Harwood, CA, Proby, CM & Leigh, IM 2018, 'The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature', Nature Communications, vol. 9, no. 1, 3667, pp. 1-14. https://doi.org/10.1038/s41467-018-06027-1

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T1 - The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature

AU - Inman, Gareth J.

AU - Wang, Jun

AU - Nagano, Ai

AU - Alexandrov, Ludmil B.

AU - Purdie, Karin J.

AU - Taylor, Richard G.

AU - Sherwood, Victoria

AU - Thomson, Jason

AU - Hogan, Sarah

AU - Spender, Lindsay C.

AU - South, Andrew P.

AU - Stratton, Michael

AU - Chelala, Claude

AU - Harwood, Catherine A.

AU - Proby, Charlotte M.

AU - Leigh, Irene M.

PY - 2018/9/10

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N2 - 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.

AB - 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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DO - 10.1038/s41467-018-06027-1

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SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3667

ER -

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

Abstract

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Proby, Charlotte

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