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

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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. [3667]. https://doi.org/10.1038/s41467-018-06027-1