Sun-Induced Nonsynonymous p53 Mutations Are Extensively Accumulated and Tolerated in Normal Appearing Human Skin

Division of Gene Technology, Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden.
Journal of Investigative Dermatology (Impact Factor: 7.22). 10/2010; 131(2):504-8. DOI: 10.1038/jid.2010.302
Source: PubMed


Here we demonstrate that intermittently sun-exposed human skin contains an extensive number of phenotypically intact cell compartments bearing missense and nonsense mutations in the p53 tumor suppressor gene. Deep sequencing of sun-exposed and shielded microdissected skin from mid-life individuals revealed that persistent p53 mutations had accumulated in 14% of all epidermal cells, with no apparent signs of a growth advantage of the affected cell compartments. Furthermore, 6% of the mutated epidermal cells encoded a truncated protein. The abundance of these events, not taking into account intron mutations and mutations in other genes that also may have functional implications, suggests an extensive tolerance of human cells to severe genetic alterations caused by UV light, with an estimated annual rate of accumulation of ∼35,000 new persistent protein-altering p53 mutations in sun-exposed skin of a human individual.

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Available from: Patrik L Ståhl, Sep 01, 2014
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    • "Considering the overall high percentages of human SCCs with UV signature mutations in P53 and NOTCH, one is led to infer that most of these tumors are induced by life-long, or at least decades of, chronic UV exposure. Even in temperate climate with low ambient UV, high frequencies of UV-related P53 and NOTCH mutations were found in sun-exposed adult skin[45,46]. We have earlier shown that in contrast to chronic UVB exposure, chronic UVA exposure of SKH1 hairless mice induced SCCs of which a large majority (85%) lacked p53 mutations[47]. "
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    Preview · Article · Jan 2016 · Oncotarget
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    • "Each target was amplified by a two-step PCR, and received a distinct index included in one of the inner primers (Figure 1b, Supplementary Table S3 and S4). The indices have been described previously2526, as well as the primers for TP53 exon 2 and 927 and the general primers for TP53 and Lambda20. Inner cycling, 94°C 5 min, [94°C 30s, 60°C 120 s, 72°C 3 min] × 10 cycles, 72°C 5 min, 4°C hold, outer cycling the same but 30 cycles. "
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    • "In skin biology and dermatology, DNA sequencing has been used primarily in melanoma research. Specifically, using deep sequencing it was shown that sun-exposed human skin contains mutations in the p53 tumor suppressor gene in up to 14% of all epidermal cells [33]. Sequencing was applied as a sensitive and cost-effective method for BRAF genotyping of melanomas from patients [34]. "
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