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

Verkler, Tracie L.; Delongchamp, Robert R.; Couch, Letha H.; Miller, Barbara J.; Warbritton, Alan; Mellick, Paul W.; Howard, Paul C.; Parsons, Barbara L.

doi:10.1002/mc.20439

Cited by 10 publications

(9 citation statements)

References 23 publications

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“…These tumors were generated as part of a separate study designed to develop methodology to document skin tumor growth in SKH‐1 mice. The measurement of p53 MF within these tumors is reported in the accompanying study 1. Differences between the p53 MFs in the skin and tumor samples were analyzed for significance using a Mann–Whitney rank sum test.…”

Section: Methodsmentioning

confidence: 99%

“…Quantification of a p53 tumor suppressor gene mutation throughout the process of simulated solar light‐induced skin carcinogenesis is being performed in order to investigate whether and how a tumor‐associated mutational biomarker can be used in cancer risk assessment. A large literature supports the idea that certain p53 mutations are major etiologic factors in the development of skin cancer and provides a foundation for investigating p53 mutation as a biomarker for sunlight‐induced skin carcinogenesis 1. Briefly, characteristic patterns of mutations (primarily C to T and CC to TT) are known to be induced by UV‐B, sunlight, and simulated solar light (SSL) 2–5.…”

Section: Introductionmentioning

confidence: 98%

“…Briefly, characteristic patterns of mutations (primarily C to T and CC to TT) are known to be induced by UV‐B, sunlight, and simulated solar light (SSL) 2–5. The p53 gene is mutated in 80–90% of human preneoplastic skin lesions, in ∼90% of human squamous cell carcinomas (SCCs), and in 60–65% of SSL or UV‐B induced mouse SSCs 1, 3, 6. Additional evidence of p53 function in skin carcinogenesis comes from the discovery that transgenic mice lacking one or both functional p53 alleles develop skin cancer sooner than mice with two normal copies of the gene 7, 8.…”

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: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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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“…First, the frequencies of spontaneous tumor-associated mutations are higher than expected based on neutral reporter gene mutant frequencies. Second, when the mutations most strongly associated with particular tumor types are measured in tumor tissue by ACB-PCR, tumor subpopulations are observed [Verkler et al, 2008a;Parsons et al, 2010].…”

Section: Lessons Learned During Initial Validation Of Oncomutation Asmentioning

confidence: 99%

“…Consequently, mutation at such sites is overrepresented in rodent and human skin tumors. One such mutation is the mouse p53 codon 270 (codon 273 in human) CGT?TGT mutation [Verkler et al, 2008a]. Because the induction of skin tumors in the hairless SKH-1 mouse by chronic exposure to SSL had previously been characterized (see Table II), the same doses of SSL were used and the induction of p53 codon 270 CGT?TGT mutation was measured at several time points preceding tumor development [Verkler et al, 2008b].…”

Section: Validation Of Oncomutations As Endpoints For Assessing Chemimentioning

confidence: 99%

Oncomutations as biomarkers of cancer risk

Parsons

Myers

Meng

et al. 2010

Environ and Mol Mutagen

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Cancer risk assessment impacts a range of societal needs, from the regulation of chemicals to achieving the best possible human health outcomes. Because oncogene and tumor suppressor gene mutations are necessary for the development of cancer, such mutations are ideal biomarkers to use in cancer risk assessment. Consequently, DNA-based methods to quantify particular tumor-associated hotspot point mutations (i.e., oncomutations) have been developed, including allele-specific competitive blocker-PCR (ACB-PCR). Several studies using ACB-PCR and model mutagens have demonstrated that significant induction of tumor-associated oncomutations are measureable at earlier time points than are used to score tumors in a bioassay. In the particular case of benzo[a]pyrene induction of K-Ras codon 12 TGT mutation in the A/J mouse lung, measurement of tumor-associated oncomutation was shown to be an earlier and more sensitive endpoint than tumor response. The measurement of oncomutation by ACB-PCR led to two unexpected findings. First, oncomutations are present in various tissues of control rodents and "normal" human colonic mucosa samples at relatively high frequencies. Approximately 60% of such samples (88/146) have mutant fractions (MFs) >10(-5), and some have MFs as high as 10(-3) or 10(-4). Second, preliminary data indicate that oncomutations are present frequently as subpopulations in tumors. These findings are integrated into a hypothesis that the predominant preexisting mutations in particular tissues may be useful as generic reporters of carcinogenesis. Future research opportunities using oncomutation as an endpoint are described, including rodent to human extrapolation, dose-response assessment, and personalized medicine.

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K‐Ras mutant fraction in A/J mouse lung increases as a function of benzo[a]pyrene dose

Meng

Knapp

Green

et al. 2009

Environ and Mol Mutagen

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K-Ras mutant fraction (MF) was measured to examine the default assumption of low-dose linearity in the benzo[a]pyrene (B[a]P) mutational response. Groups of 10 male A/J mice (7- to 9-weeks old) received a single i.p. injection of 0, 0.05, 0.5, 5, or 50 mg/kg B[a]P and were sacrificed 28 days after treatment. K-Ras codon 12 TGT and GAT MFs in lung DNAs were measured using Allele-specific Competitive Blocker-PCR (ACB-PCR). The K-Ras codon 12 TGT geometric mean MF was 3.88 x 10(-4) in controls, indicating an average of 1 mutation in every approximately 1,288 lung cells. The K-Ras codon 12 TGT geometric mean MFs were as follows: 3.56 x 10(-4); 6.19 x 10(-4); 2.02 x 10(-3), and 3.50 x 10(-3) for the 0.05, 0.5, 5, and 50 mg/kg B[a]P treatment groups, respectively. The 5 and 50 mg/kg dose groups had TGT MFs significantly higher than did controls. Although 10(-5) is considered as the limit of accurate ACB-PCR quantitation, K-Ras codon 12 GAT geometric mean MFs were as follows: 8.38 x 10(-7), 1.47 x 10(-6), 2.19 x 10(-6), 5.71 x 10(-6), and 8.99 x 10(-6) for the 0, 0.05, 0.5, 5, and 50 mg/kg B[a]P treatment groups, respectively. The K-Ras TGT and GAT MFs increased in a B[a]P-dose-dependent manner, with response approximately linear over the 0.05 to 5 mg/kg dose range. K-Ras MF increased with B[a]P adduct burden measured for identical doses in a separate study. Thus, ACB-PCR may be useful in characterizing the shape of a dose-response curve at low doses and establishing relationships between DNA adducts and tumor-associated mutations.

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

Cited by 10 publications

References 23 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

Oncomutations as biomarkers of cancer risk

K‐Ras mutant fraction in A/J mouse lung increases as a function of benzo[a]pyrene dose

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