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

Inman, G. J. et al. (2018) The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. Nature Communications, 9, 3667. (doi: 10.1038/s41467-018-06027-1) (PMID:30202019) (PMCID:PMC6131170)

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.

• Item Type: Articles
• Additional Information: G.J.I., K.J.P., V.S., A.P.S., C.A.H, C.M.P., and I.M.L. acknowledge support from Cancer Research UK programme grant (A13044) and a European Research Council Grant (250170). R.G.T was supported by a Cancer Research UK (Clinical PhD Fellowship/Centre grant (A12976). L.C.S. was supported by Worldwide Cancer Research grant (11-0788). J.W., A.N. and C.C. acknowledge support from Cancer Research UK Centre of Excellence Award to Barts Cancer Centre [C16420/A18066].
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Inman, Professor Gareth
• Authors: 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., and Leigh, I. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Nature Communications 9:3667
• Publisher Policy: Reproduced under a Creative Commons License