Frequent <i>p</i>53 alterations but low incidence of <i>ras</i> mutations in UV-B-induced skin tumors of hairless mice

Kranen, Henk J. van; Gruijl, Frank R. de; Vries, Annemieke de; Sontag, Y.; Wester, Piet W.; Senden, H. C. M.; Rozemuller, Erik H.; Kreijl, Coen F. van

doi:10.1093/carcin/16.5.1141

Cited by 95 publications

(82 citation statements)

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“…The prevalence of p53 protein overexpression in UV-induced skin cancer ranged from 20% to 80% in previous reports (Nagano et al, 1993;van Kranen et al, 1995van Kranen et al, , 1997Berg et al, 1996;Nataraj et al, 1996). The significant positive rate in Bowen's disease patients suggested that p53 gene mutation commonly occurred in the early stages of arsenic-related skin cancer.…”

Section: Discussionmentioning

confidence: 89%

Mutational spectrum of p53 gene in arsenic-related skin cancers from the blackfoot disease endemic area of Taiwan

et al. 1999

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SummaryTo understand the role of p53 tumour suppressor gene in the carcinogenesis of arsenic-related skin cancers from the blackfoot disease endemic area of Taiwan, we collected tumour samples from 23 patients with Bowen's disease, seven patients with basal cell carcinomas (BCC) and nine patients with squamous cell carcinomas (SCC). The result showed that p53 gene mutations were found in 39% of cases with Bowen's disease (9/23), 28.6% of cases with BCC (2/7) and 55.6% of cases with SCC (5/9). Most of the mutation sites were located on exon 5 and exon 8. Moreover, the results from direct sequencing indicated that missense mutations were found at codon 149 (C→T) in one case, codon 175 (G→A) in three cases, codon 273 (G→C) in three cases, codon 292 (T→A) in one case, codon 283 (G→T) in one case, codon 172 (T→C) in one case and codon 284 (C→A) in one case. In addition, silent mutations were also found in four cases. These mutations were located at codons 174, 253, 289 and 298 respectively. In immunohistochemistry analysis, p53 overexpression was found in 43.5% (10/23) of cases with Bowen's disease, 14% (1/7) of cases with BCC and 44% (4/9) of cases with SSC. These findings showed that p53 gene mutation rate in arsenic-related skin cancers from the blackfoot disease endemic area of Taiwan is high and that the mutation types are different from those in UV-induced skin cancers.

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Section: Discussionmentioning

confidence: 89%

Mutational spectrum of p53 gene in arsenic-related skin cancers from the blackfoot disease endemic area of Taiwan

et al. 1999

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“…UV-induced skin tumors in NER-proficient mice expressed a very typical mutation spectrum at p53. The great majority of the mutations are found at dipyrimidine sites at the non-transcribed strand (NTS) [114], [115], [116], [117], [118] and [119]. In NER-deficient mice, the prevalence of p53 mutations in the TS versus NTS is dependent on the specific pathway which is absent.…”

Section: Skinmentioning

confidence: 99%

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

Wijnhoven

Hoogervorst

Waard

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) areexcept for the skin -not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features.

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“…A role for sun exposure in the induction of the p53 mutations is indicated by the notion that the mutations are almost exclusively C to T or CC to TT transitions at dipyrimidine sites, both hallmarks of UV-induced DNA damage (Brash et al, 1991;Kress et al, 1992;Kanjilal et al, 1993;Ziegler et al, 1993). Moreover, in an animal model, frequent alterations in the p53 gene have been noticed in tumours caused by UV-B treatment (Kanjilal et al, 1993;van Kranen et al, 1995).…”

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confidence: 99%

p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

et al. 1999

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SummaryIn melanoma, the relationship between sun exposure and the origin of mutations in either the N-ras oncogene or the p53 tumoursuppressor gene is not as clear as in other types of skin cancer. We have previously shown that mutations in the N-ras gene occur more frequently in melanomas originating from sun-exposed body sites, indicating that these mutations are UV induced. To investigate whether sun exposure also affects p53 in melanoma, we analysed 81 melanoma specimens for mutations in the p53 gene. The mutation frequency is higher than thus far reported: 17 specimens (21%) harbour one or more p53 mutations. Strikingly, 17 out of 22 mutations in p53 are of the C:G to T:A or CC:GG to TT:AA transitional type, strongly suggesting an aetiology involving UV exposure. Interestingly, the p53 mutation frequency in metastases was much lower than in primary tumours. In the case of metastases, a role for sun exposure was indicated by the finding that the mutations are present exclusively in skin metastases and not in internal metastases. Together with a relatively frequent occurrence of silent third-base pair mutations in primary melanomas, this indicates that the p53 mutations, at least in these tumours, have not contributed to melanomagenesis and may have originated after establishment of the primary tumour.

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Frequent p53 alterations but low incidence of ras mutations in UV-B-induced skin tumors of hairless mice

Cited by 95 publications

References 0 publications

Mutational spectrum of p53 gene in arsenic-related skin cancers from the blackfoot disease endemic area of Taiwan

Mutational spectrum of p53 gene in arsenic-related skin cancers from the blackfoot disease endemic area of Taiwan

Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

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