Aberrations of the Tumor Suppressor p53 Gene and p53 Protein in Solar Keratosis in Human Skin

Taguchi, Masahito; Watanabe, Shaw; Yashima, Kazuo; Murakami, Yoshinori; Sekiya, Takao; Ikedat, Shigeo

doi:10.1111/1523-1747.ep12395643

Cited by 64 publications

(36 citation statements)

References 23 publications

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“…The prevalence of C:G to T:A or CC:GG to TT:AA transitions at dipyrimidine sites (presumably related to UVR) was 4 out of 10 in SCCs and BCCs (Kubo et al, 1994), 6 out of 15 in BCCs (Matsumura et al, 1996) and 3 out of 8 in actinic keratoses (Taguchi et al, 1994). We identified 2 additional CC:GG to TT:AA tandem mutations in a total of 9 mutations found in Japanese Bowen's disease.…”

Section: Discussionmentioning

confidence: 84%

p53 mutation spectrum in Japanese Bowen's disease suggests a role for mutagens other than ultraviolet light

1997

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The Japanese have a much lower incidence of nonmelanoma skin cancers (NMSCs) than Caucasians, presumably due in part to their skin type conferring relative protection from ultraviolet light radiation (UVR). To examine the contribution of environmental or endogenous mutagens other than UVR, which are expected to be relatively more important to the overall burden of NMSCs in the Japanese, we directly sequenced exons 5-8 of the p53 tumour suppressor gene in 29 Japanese patients with Bowen's disease, an in situ squamous-cell carcinoma of the skin. We found 9 mutations, including two CC:GG to TT:AA tandem transitions (presumably related to UVR), 3 transversions and 4 frameshift mutations. The mutational spectrum seen in our study contrasts with that we previously found in Bowen's disease from a Caucasian population, in keeping with a different aetiology for Bowen's disease in the respective populations. The unexpectedly high prevalence of frameshift mutations suggests that environmental mutagens other than UVR that preferentially induce deletion or insertion mutations may play an important role in the tumorigenesis of Japanese Bowen's disease, and warrants further investigation.

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Section: Discussionmentioning

confidence: 84%

p53 mutation spectrum in Japanese Bowen's disease suggests a role for mutagens other than ultraviolet light

1997

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“…Cells with extensive damage are blocked from entering the cell cycle and instead undergo apoptosis (15,16). Mutation of p53 disrupts this process, often leading to a stabilization of the protein (12,13,16,(23)(24)(25)(26)(27)(28)(29)(30)(31). We previously reported that p53 expression was in fairly good agreement with the presence of p53 mutations (21) and that the frequency of p53 mutations and expression increases between upper inner arm skin, skin adjacent to an AK, but that AK and SCC were similar (22).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations of the p53 gene occur early in the sequential development of chronically sun-damaged skin, AK, and SCC (8)(9)(10)(11)(12)(13)(14), strongly supporting an important role for p53 in UVinduced skin carcinogenesis. The p53 gene is essential in maintaining genomic integrity by blocking DNA replication in response to DNA damage from exposure to agents like UV light.…”

Section: Introductionmentioning

confidence: 94%

Reproducibility and Expression of Skin Biomarkers in Sun-Damaged Skin and Actinic Keratoses

Einspahr

Warneke³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Objectives: To explore p53 and proliferating cell nuclear antigen (PCNA) expression and polyamine content as biomarkers in skin cancer chemoprevention trials, we evaluated their expression in early stages of UV-induced squamous cell tumorigenesis. Methods: Biopsies were collected from three groups: 78 subjects with sun damage on forearms, 33 with actinic keratosis (AK) on forearms, and 32 with previous squamous cell carcinoma. Participants with sun damage were randomized to sunscreen or no sunscreen. Results: We found significant differences in p53 and polyamines in forearms from the sun-damaged group (11.5 F 1.2% for p53, 65.5 F 1.9 nmol/g for putrescine, and 187.7 F 3.3 nmol/g for spermidine) compared with the group with sun damage plus AK (20.9 F 2.3% for p53, P = 0.0001; 81.7 F 3.9 nmol/g for putrescine, P = 0.0001; 209.4 F 8.2 nmol/g for spermidine, P < 0.06). PCNA was not different. When lesion histology was considered, there was a stepwise significant increase in p53 in biopsies without characteristics of AK compared with early AK (P = 0.02) and AK (P = 0.0006) and a similar pattern for PCNA with the only significant difference between early AK and AK. There was a stepwise increase in putrescine and spermidine in normal, sun-damaged forearm, forearm from subjects with AK, and the AK lesion itself (P < 0.0001). No significant differences in p53 or polyamines were seen in 3-month biopsies or, as a result of sunscreen use, although PCNA in the sun-damaged group not using sunscreen decreased significantly. Conclusions: p53 expression and polyamines in skin were elevated in early stages of skin tumorigenesis and were not affected by sunscreen, adding validity to their use as biomarkers in skin cancer chemoprevention trials. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1841 -8)

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“…This early role of sunlight is supported by the finding of sunlightinduced mutations in the p53 tumor suppressor gene in actinic keratosis, the precancerous lesion for squamous cell carcinoma of the skin. In addition, p53-mutated cells are present in skin flanking human tumors and in UV-irradiated mouse skin (3)(4)(5)(6)(7)(8). Mutations at particular p53 codons are present in sun-exposed normal human skin at frequencies of 10 Ϫ6 to 10 Ϫ2 (5, 9).…”

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confidence: 99%

Frequent clones of p53-mutated keratinocytes in normal human skin

Jonason

Subrahmanyam

Price

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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The multiple genetic hit model of cancer predicts that normal individuals should have stable populations of cancer-prone, but noncancerous, mutant cells awaiting further genetic hits. We report that whole-mount preparations of human skin contain clonal patches of p53-mutated keratinocytes, arising from the dermal-epidermal junction and from hair follicles. These clones, 60-3000 cells in size, are present at frequencies exceeding 40 cells per cm 2 and together involve as much as 4% of the epidermis. In sun-exposed skin, clones are both more frequent and larger than in sun-shielded skin. We conclude that, in addition to being a tumorigenic mutagen, sunlight acts as a tumor promoter by favoring the clonal expansion of p53-mutated cells. These combined actions of sunlight result in normal individuals carrying a substantial burden of keratinocytes predisposed to cancer.Although skin cancers typically arise in patients aged 50-70, epidemiologic evidence indicates that much of the critical sunlight exposure is received before the age of 18 (1, 2). This early role of sunlight is supported by the finding of sunlightinduced mutations in the p53 tumor suppressor gene in actinic keratosis, the precancerous lesion for squamous cell carcinoma of the skin. In addition, p53-mutated cells are present in skin flanking human tumors and in UV-irradiated mouse skin (3-8). Mutations at particular p53 codons are present in sun-exposed normal human skin at frequencies of 10 Ϫ6 to 10 Ϫ2 (5, 9). Other human tumors for which mutation of p53 appears to be an early event include head and neck cancer and hepatocellular carcinoma (10, 11).Because keratinocytes are continuously lost through squamous differentiation and desquamation, it seems likely that the cell targeted by sunlight decades before a tumor's appearance is a stem cell. If so, the keratinocytes containing the mutations measured in normal skin would not be randomly dispersed but instead would reside in clonal patches arising from mutated stem cells. The frequency of p53 mutations measured in a biopsy of normal skin would then depend on whether the biopsy included a clone. The spatial arrangement of the cells in the clone might give clues to the geometry of early carcinogenesis, including the site of the stem cells from which skin tumors originate in humans.We therefore devised a whole-mount preparation method for human epidermis that permitted immunohistochemical analysis for stabilized p53 protein. A p53 mutation usually leads to nuclear immunopositivity (12). A large enough sample of skin might contain rare patches staining intensely for p53. We report here that such patches are not only present and contain mutations but are also frequent, indicating the existence of a large population of cells in normal skin that are presumably predisposed to skin cancer. In addition, we present evidence that sunlight can act both as a tumor initiator and as a tumor promoter for p53-mutated cells. MATERIALS AND METHODSEpidermal Whole Mounts. Fresh skin samples were obtained from discard...

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Aberrations of the Tumor Suppressor p53 Gene and p53 Protein in Solar Keratosis in Human Skin

Cited by 64 publications

References 23 publications

p53 mutation spectrum in Japanese Bowen's disease suggests a role for mutagens other than ultraviolet light

p53 mutation spectrum in Japanese Bowen's disease suggests a role for mutagens other than ultraviolet light

Reproducibility and Expression of Skin Biomarkers in Sun-Damaged Skin and Actinic Keratoses

Frequent clones of p53-mutated keratinocytes in normal human skin

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