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

• Published in: Nature communications Vol. 9; no. 1; pp. 3667 - 14
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.09.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/61; 3T3 Cells; 45; 45/23; 631/67/1813/1352; 631/67/69; Animals; Azathioprine; Azathioprine - therapeutic use; Biopsy; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Cell Differentiation; Cell Line, Tumor; Chronic exposure; Copy number; Correlation analysis; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; Drug Screening Assays, Antitumor; Exome; Gene Dosage; Gene expression; Gene Expression Profiling; Genomics; Humanities and Social Sciences; Humans; Immunosuppressive agents; Immunosuppressive Agents - therapeutic use; Longitudinal Studies; Mice; multidisciplinary; Mutation; Prognosis; Science; Science (multidisciplinary); Sequence Analysis, DNA; Signature analysis; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Squamous cell carcinoma; Therapeutic applications; Tumor cell lines; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06027-1

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. It is known cutaneous squamous cell carcinoma (cSCC) involves a high tumour mutation burden. Here the authors identify common cSCC mutated genes, copy number changes, altered pathways and report the presence of a novel mutation signature associated with chronic exposure to the immunosuppressive drug azathioprine.