title: Whole-Exome Sequencing Validates a Preclinical Mouse Model for the Prevention and Treatment of Cutaneous Squamous Cell Carcinoma.
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. Whole-exome 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.G>T.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. Cancer Prev Res; 10(1); 67-75. ©2016 AACR.
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Scotland, United Kingdom.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Knatko
authors.affiliation: Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Praslicka
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Scotland, United Kingdom.
authors.forename: Maureen
authors.initials: M
authors.lastname: Higgins
authors.affiliation: Department of Pathology, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Evans
authors.affiliation: Centre for Cutaneous Research, Barts and the London Queen Mary University of London, London, United Kingdom.
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Purdie
authors.affiliation: Centre for Cutaneous Research, Barts and the London Queen Mary University of London, London, United Kingdom.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Harwood
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Scotland, United Kingdom.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Proby
authors.affiliation: Department of Toxicology and Pharmacology, College of Pharmacy, University of Arizona. Tucson, Arizona, USA.
authors.forename: Aikseng
authors.initials: A
authors.lastname: Ooi
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Scotland, United Kingdom.|Department Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004252:DNA Mutational Analysis / Q000379:methods; D059472:Exome; D005260:Female; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D000072417:Protein Domains / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D051880:Receptors, Notch; D016159:Tumor Suppressor Protein p53