Whole-exome sequencing validates a preclinical mouse model for the prevention and treatment of cutaneous squamous cell carcinoma

Elena V. Knatko, Brandon Praslicka, Maureen Higgins, Alan Evans, Karin J. Purdie, Catherine A. Harwood, Charlotte M. Proby, Aikseng Ooi (Lead / Corresponding author), Albena T. Dinkova-Kostova (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    9 Citations (Scopus)
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    Abstract

    Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies. Solar UV radiation is the major factor in the etiology of cSCC. Wholeexome sequencing of 18 microdissected tumor samples (cases) derived from SKH-1 hairless mice that had been chronically exposed to solar-simulated UV (SSUV) radiation showed a median point mutation (SNP) rate of 155 per Mb. The majority (78.6%) of the SNPs are C.GT.A transitions, a characteristic UVR-induced mutational signature. Direct comparison with human cSCC cases showed high overlap in terms of both frequency and type of SNP mutations. Mutations in Trp53 were detected in 15 of 18 (83%) cases, with 20 of 21 SNP mutations located in the protein DNA-binding domain. Strikingly, multiple nonsynonymous SNP mutations in genes encoding Notch family members (Notch1-4) were present in 10 of 18 (55%) cases. The histopathologic spectrum of the mouse cSCC that develops in this model resembles very closely the spectrum of human cSCC. We conclude that the mouse SSUV cSCCs accurately represent the histopathologic and mutational spectra of the most prevalent tumor suppressors of human cSCC, validating the use of this preclinical model for the prevention and treatment of human cSCC.

    Original languageEnglish
    Pages (from-to)67-75
    Number of pages9
    JournalCancer Prevention Research
    Volume10
    Issue number1
    Early online date6 Dec 2016
    DOIs
    Publication statusPublished - Jan 2017

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