ABSTRACT
Squamous cell carcinoma in situ (SCCIS) is a prevalent precancerous lesion that can progress to cutaneous squamous cell carcinoma. Although SCCIS is common, its pathogenesis remains poorly understood. To better understand SCCIS development, we performed laser captured microdissection of human SCCIS and the adjacent epidermis to isolate genomic DNA and RNA for next-generation sequencing. Whole-exome sequencing identified UV-signature mutations in multiple genes, including NOTCH1-3 in the epidermis and SCCIS and oncogenic TP53 mutations in SCCIS. Gene families, including SLFN genes, contained UV/oxidative-signature disruptive epidermal mutations that manifested positive selection in SCCIS. The frequency and distribution of NOTCH and TP53 mutations indicate that NOTCH mutations may precede TP53 mutations. RNA sequencing identified 1,166 differentially expressed genes; the top five enriched gene ontology biological processes included (i) immune response, (ii) epidermal development, (iii) protein phosphorylation, (iv) regulation of catalytic activity, and (v) cytoskeletal regulation. The NEURL1 ubiquitin ligase, which targets Notch ligands for degradation, was upregulated in SCCIS. NEURL1 protein was found to be elevated in SCCIS suggesting that increased levels could represent a mechanism for downregulating Notch during UV-induced carcinogenesis. The data from DNA and RNA sequencing of epidermis and SCCIS provide insights regarding SCCIS formation.
Subject(s)
Carcinoma in Situ/etiology , Carcinoma, Squamous Cell/etiology , Epidermis/radiation effects , Exome , Gene Expression Profiling , Neoplasms, Radiation-Induced/etiology , Skin Neoplasms/etiology , Carcinogenesis/genetics , Carcinoma in Situ/genetics , Carcinoma, Squamous Cell/genetics , Genes, p53 , Humans , Mutation , Neoplasms, Radiation-Induced/genetics , Receptors, Notch/genetics , Sequence Analysis, RNA , Skin Neoplasms/genetics , Ultraviolet RaysABSTRACT
The American Cancer Society estimates that skin cancer is the most prevalent of all cancers with over 2 million cases of nonmelanoma skin cancer each year and 75,000 melanoma cases in 2012. Representative animal cancer models are important for understanding the underlying molecular pathogenesis of these cancers and the development of novel targeted anticancer therapeutics. In this review, we will discuss some of the important animal models that have been useful to identify important pathways involved in basal cell carcinoma, squamous cell carcinoma, and melanoma.
