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 and Irene M. Leigh ()
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Gareth J. Inman: University of Dundee
Jun Wang: Queen Mary University of London
Ai Nagano: Queen Mary University of London
Ludmil B. Alexandrov: University of California, San Diego
Karin J. Purdie: Queen Mary University of London
Richard G. Taylor: University of Dundee
Victoria Sherwood: University of Dundee
Jason Thomson: Queen Mary University of London
Sarah Hogan: Queen Mary University of London
Lindsay C. Spender: University of Dundee
Andrew P. South: Thomas Jefferson University
Michael Stratton: Cancer Genome Project, Wellcome Trust Sanger Institute
Claude Chelala: Queen Mary University of London
Catherine A. Harwood: Queen Mary University of London
Charlotte M. Proby: University of Dundee
Irene M. Leigh: University of Dundee

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06027-1

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