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 languageEnglish
Article number3667
Pages (from-to)1-14
Number of pages14
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 10 Sep 2018

Fingerprint

Azathioprine
Tumors
tumors
signatures
Skin
Squamous Cell Carcinoma
Neoplasms
cancer
Exome
Gene Dosage
signature analysis
Immunosuppressive Agents
Tumor Burden
Tumor Cell Line
Longitudinal Studies
Disease Progression
gene expression
mutations
cultured cells
Gene expression

Cite this

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. In: Nature Communications. 2018 ; Vol. 9, No. 1. pp. 1-14.
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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.",
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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

The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. / Inman, Gareth J. (Lead / Corresponding author); Wang, Jun (Lead / Corresponding author); 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. (Lead / Corresponding author).

In: Nature Communications, Vol. 9, No. 1, 3667, 10.09.2018, p. 1-14.

Research output: Contribution to journalArticle

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AU - Inman, Gareth J.

AU - Wang, Jun

AU - Nagano, Ai

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AU - Purdie, Karin J.

AU - Taylor, Richard G.

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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.

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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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