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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 S, 2018. "The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06027-1
    DOI: 10.1038/s41467-018-06027-1
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    Cited by:

    1. Peter Bailey & Rachel A. Ridgway & Patrizia Cammareri & Mairi Treanor-Taylor & Ulla-Maja Bailey & Christina Schoenherr & Max Bone & Daniel Schreyer & Karin Purdie & Jason Thomson & William Rickaby & R, 2023. "Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Lucia Morgado-Palacin & Jessie A. Brown & Thomas F. Martinez & Juana M. Garcia-Pedrero & Farhad Forouhar & S. Aidan Quinn & Clara Reglero & Joan Vaughan & Yasamin Hajy Heydary & Cynthia Donaldson & Sa, 2023. "The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Annarita Nappi & Caterina Miro & Antonio Pezone & Alfonso Tramontano & Emery Cicco & Serena Sagliocchi & Annunziata Gaetana Cicatiello & Melania Murolo & Sepehr Torabinejad & Elena Abbotto & Giuseppin, 2023. "Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Frederic Li Mow Chee & Bruno Beernaert & Billie G. C. Griffith & Alexander E. P. Loftus & Yatendra Kumar & Jimi C. Wills & Martin Lee & Jessica Valli & Ann P. Wheeler & J. Douglas Armstrong & Maddy Pa, 2023. "Mena regulates nesprin-2 to control actin–nuclear lamina associations, trans-nuclear membrane signalling and gene expression," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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