<i>p53</i> Mutations in Hairless SKH‐hr1 Mouse Skin Tumors Induced by a Solar Simulator

Ananthaswamy, Honnavara N.; Fourtanier, Anny; Evans, Robert B.; Tison, Sylvie; Medaisko, Chantal; Ullrich, Stephen E.; Kripke, Margaret L.

doi:10.1111/j.1751-1097.1998.tb05191.x

Cited by 18 publications

(20 citation statements)

References 21 publications

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“…Epidemiological and molecular studies have implicated the UV components of sunlight as the major etiologic factor in the development of nonmelanoma skin cancer. Major effects of radiation are erythema, immunosuppression and mutation, particularly p53 mutation 4, 13, 24, 25. Despite widespread acceptance that p53 mutation is a key determinate in skin carcinogenesis, p53 mutation has not been validated as a quantitative biomarker of nonmelanoma skin cancer development.…”

Section: Discussionmentioning

confidence: 99%

“…Methods used to detect p53 mutations generally lack quantitative capability. DNA sequencing, single stranded conformation polymorphism, denaturing gradient gel electrophoresis, and allele‐specific polymerase chain reaction are the methods that have been applied to the detection of p53 mutation 4, 8, 11, 13, 14, 24. Although these methods vary in sensitivity, each method reports only the presence or absence of mutation in a particular DNA sample 26.…”

Section: Discussionmentioning

confidence: 99%

“…ACB‐PCR is an assay that has been developed to quantify the levels of a particular point mutation within the population of DNA molecules isolated from a tissue sample. The mouse p53 codon 270 CGT to TGT mutation was selected as the target mutation in this assay because it is a dominant‐negative p53 mutation (meaning a single mutant copy is sufficient to produce the mutant phenotype) and is detected more often than any other p53 mutation in UV‐ or SSL‐induced skin tumors of the SKH‐1 hairless mouse 9, 13, 14. ACB‐PCR is a sensitive method that can quantify levels of a mutation, even when mutant DNA is present within a 100 000‐fold excess of wild‐type DNA 15, 16.…”

Section: Introductionmentioning

confidence: 99%

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Simulated solar light‐induced p53 mutagenesis in SKH‐1 mouse skin: A dose–response assessment

Verkler

Delongchamp

Miller

et al. 2008

Molecular Carcinogenesis

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Sunlight and ultraviolet-induced mutation of the p53 gene is a frequent, possibly obligate step in skin cancer development, making quantitative measurement of p53 mutation an ideal biomarker for sunlight-induced skin carcinogenesis. To understand how the appearance of p53 mutation relates to skin tumor development, SKH-1 hairless mice were exposed 5 d per week to one of four different doses of simulated solar light (SSL; 0, 6.85, 13.70, 20.55 mJ x CIE/cm(2)) previously characterized for their tumorigenic potential. Allele-specific competitive blocker-PCR (ACB-PCR) was used to measure levels of p53 codon 270 CGT to TGT mutation within DNA isolated from dorsal skin of exposed mice. For each dose, p53 mutant fraction (MF) was measured after 4, 16, and 28 wk of exposure. Significant dose- and time-dependent increases in p53 MF were identified. All p53 MF measurements were integrated by relating the observed p53 MF to the cumulative dose of SSL. The increase in the logarithm of p53 MF was described by the linear function: log(10) MF = alpha + 0.0016 x d, where alpha is the spontaneous log(10) MF after a particular time point and d is the dose of SSL in mJ x CIE/cm(2). The p53 MF induced in nontumor bearing skin by 28 wk of exposure at the high dose of SSL was significantly lower than that found in skin tumors induced by approximately 32 wk of exposure to the same dose of SSL. p53 MF showed a strong negative correlation with tumor latency, suggesting this quantitative biomarker has the potential to predict tumorigenicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Simulated solar light‐induced p53 mutagenesis in SKH‐1 mouse skin: A dose–response assessment

Verkler

Delongchamp

Miller

et al. 2008

Molecular Carcinogenesis

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“…p53 mutation has been detected in 60% of the UV‐B‐induced SCCs and 65% of the SSL‐induced SCCs of the SKH‐1 mouse [data compiled from 9, 10, 15–18]. The p53 codon 270 CGT to TGT mutation (where the C is part of a dipyrimidine sequence, specifically TCGT), in particular, was detected in 40% (26/40) of SCCs induced by SSL in SKH‐1 mice, as measured by PCR‐single‐strand conformation polymorphism (SSCP) and DNA sequencing 17, 18. The remarkable finding that a single base substitution is detected in such a significant proportion of mouse skin tumors strongly suggests that (1) the mouse codon 270 mutation might provide a powerful selective advantage to mutant cells, and (2) this mutation may be a sensitive biomarker of cancer risk from exposure to sunlight.…”

Section: Introductionmentioning

confidence: 99%

Populations of p53 codon 270 CGT to TGT mutant cells in SKH‐1 mouse skin tumors induced by simulated solar light

Verkler

Delongchamp

Couch

et al. 2008

Molecular Carcinogenesis

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The p53 codon 270 CGT to TGT mutation was investigated as a biomarker of sunlight-induced mutagenesis and carcinogenesis. The relationship between tumor development and abundance of this hotspot mutation was analyzed in mouse skin tumors induced by chronic exposure to simulated solar light (SSL). The 24 tumors analyzed had similar growth kinetics, with an average doubling time of approximately 16.4 d. Levels of the p53 codon 270 mutation were quantified in the 24 mouse skin tumors using allele-specific competitive blocker-polymerase chain reaction (ACB-PCR). All tumors contained measurable amounts of the mutation. The p53 codon 270 CGT to TGT mutant fraction (MF) ranged from 2.29 x 10(-3) to 9.42 x 10(-2), with 3.26 x 10(-2) as the median. These p53 MF measurements are lower than expected for an initiating mutation involved in the development of tumors of monoclonal origin. There was no evidence of a correlation between p53 codon 270 MF and either tumor area or an estimate of tumor cell number. Thus, the data do not support the idea that p53 mutation accumulates linearly during tumor development. To investigate how p53 mutation was distributed within tumors, 19 needle biopsies from seven different tumors were analyzed by ACB-PCR. This analysis demonstrated that p53 codon 270 mutation is heterogeneously distributed within tumors. The long-term goal of this research is to combine morphological and p53 MF measurements from tissues corresponding to the various stages of tumor development, in order to derive mathematical models relating the p53 codon 270 mutation to the development of SSL-induced skin tumors.

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“…Several studies have shown that human BCCs and SCCs harbour unique mutations in p53 that are not commonly found in other human cancers. The presence of C to T and CC to TT transitions at dipyrimidine sequences, termed ‘UV signature’ mutations, provides strong evidence that UV radiation in sunlight is responsible for the induction of NMSC 15–20 . In addition, the finding that p53 mutations are present in actinic keratosis (AK) and in sun‐damaged human skin suggests that p53 mutations arise early during the development of NMSC 5,21,22 .…”

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confidence: 99%

Loss of CDKN2A and p14ARF expression occurs frequently in human nonmelanoma skin cancers

Pacifico

Peris

et al. 2007

British Journal of Dermatology

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Background The CDKN2A locus on human chromosome 9p21 encodes two proteins named p16 INK4a and p14 ARF , known to function as tumour suppressors via the retinoblastoma (Rb) or the p53 pathway. The p53 tumour suppressor gene is the most commonly mutated gene in human and mouse cancers. Disruption of the p53 and Rb pathways is a fundamental trend of most human cancer cells. Recent studies have shown that the CDKN2A gene plays an active role in the p53 and Rb tumour suppressor pathways. Genetic abnormalities in CDKN2A have been well documented in human melanoma, but their involvement in nonmelanoma skin cancer (NMSC) is less clear. Objectives To determine whether genetic abnormalities in CDKN2A and p53 genes play a role in the development of NMSC. Methods We analysed 40 primary NMSCs in 40 patients (21 squamous cell carcinomas, 17 basal cell carcinomas and two actinic keratoses) for p16 INK4a and p14 ARF protein expression and for genetic alterations in exons 1a, 1b and 2 of CDKN2A. Results Immunohistochemical analysis revealed loss of expression of p16 INK4a and p14 ARF proteins in 38 and 39 of 40 NMSCs, respectively. Amplification of genomic DNA by polymerase chain reaction revealed homozygous deletion of exon 1b in 20% of tumours and of exon 2 in 82AE5% of tumours. Of 22 NMSCs with p53 mutations, 13 (59%) had ultraviolet (UV) signature mutations in the p53 gene; all of them were strongly positive for p53 immunostaining.Conclusions In addition to mutations in the p53 gene, loss of expression of CDKN2A via deletion also plays an important role in the pathogenesis of human NMSC. While p53 mutations are induced by UVB, deletions in CDKN2A could arise spontaneously, perhaps during tumour progression.

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p53 Mutations in Hairless SKH‐hr1 Mouse Skin Tumors Induced by a Solar Simulator

Cited by 18 publications

References 21 publications

Simulated solar light‐induced p53 mutagenesis in SKH‐1 mouse skin: A dose–response assessment

Simulated solar light‐induced p53 mutagenesis in SKH‐1 mouse skin: A dose–response assessment

Populations of p53 codon 270 CGT to TGT mutant cells in SKH‐1 mouse skin tumors induced by simulated solar light

Loss of CDKN2A and p14ARF expression occurs frequently in human nonmelanoma skin cancers

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