Abstract
Nonmelanoma skin cancer (NMSC) is by far the most frequent type of cancer in humans. NMSC includes several types of malignancies with different clinical outcomes, the most frequent being basal and squamous cell carcinomas. We have used the Sleeping Beauty transposon/transposase system to identify somatic mutations associated with NMSC. Transgenic mice bearing multiple copies of a mutagenic Sleeping Beauty transposon T2Onc2 and expressing the SB11 transposase under the transcriptional control of regulatory elements from the keratin K5 promoter were treated with TPA, either in wild-type or Ha-ras mutated backgrounds. After several weeks of treatment, mice with transposition developed more malignant tumors with decreased latency compared with control mice. Transposon/transposase animals also developed basal cell carcinomas. Genetic analysis of the transposon integration sites in the tumors identified several genes recurrently mutated in different tumor samples, which may represent novel candidate cancer genes. We observed alterations in the expression levels of some of these genes in human tumors. Our results show that inactivating mutations in Notch1 and Nsd1, among others, may have an important role in skin carcinogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinogens / toxicity
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Carcinoma, Basal Cell / genetics*
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Carcinoma, Basal Cell / pathology
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / pathology
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Carrier Proteins / genetics
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Cell Transformation, Neoplastic / genetics*
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DNA Mutational Analysis / methods
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DNA Transposable Elements / genetics*
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Genes, ras / genetics
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Keratin-15
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Keratin-5 / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Mice, Transgenic
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Mutation*
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Nuclear Proteins / genetics
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Promoter Regions, Genetic
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Receptor, Notch1 / genetics
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Skin Neoplasms / genetics*
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Skin Neoplasms / pathology
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Tetradecanoylphorbol Acetate / toxicity
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Transposases / genetics
Substances
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Carcinogens
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Carrier Proteins
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DNA Transposable Elements
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Intracellular Signaling Peptides and Proteins
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Keratin-15
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Keratin-5
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Krt15 protein, mouse
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NOTCH1 protein, human
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Notch1 protein, mouse
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Nuclear Proteins
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Receptor, Notch1
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase
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NSD1 protein, human
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Nsd1 protein, mouse
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Transposases
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sleeping beauty transposase, human
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Tetradecanoylphorbol Acetate