UV-Radiation-Specific p53 Mutation Frequency in Normal Skin as a Predictor of Risk of Basal Cell Carcinoma

Ouhtit, Allal; Nakazawa, Hisayoshi; Armstrong, Bruce K.; Kricker, Anne; Tan, Ernest; Yamasaki, Hiroshi; English, Dallas R.

doi:10.1093/jnci/90.7.523

Cited by 81 publications

(67 citation statements)

References 29 publications

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“…In many cancers the p53 response is impaired late in tumorigenesis. However, in histologically normal UV-exposed skin, fields of p53 mutated cells are detectable indicating p53 alteration is early in NMSC (Ren et al, 1997;Ouhtit et al, 1998). If these cells propagate with a permissive p53 background an increase in genetic instability would be expected.…”

Section: Discussionmentioning

confidence: 99%

Microsatellite instability at tetranucleotide repeats in skin and bladder cancer

et al. 2002

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Recently, a novel form of MSI has been described that occurs only at tetranucleotide repeat markers. This has been termed elevated microsatellite instability at selected tetranucleotide repeats (EMAST). EMAST has been related to alterations of the p53 gene, and to the nature of the repeat sequence. We initially tested whether loss of heterozygosity (LOH) at the p53 and the patched (ptch) genes was related to EMAST in a series of 61 non-melanoma skin cancer (NMSC) tumors. We then analysed a series of 57 primary bladder cancers for the presence of EMAST, testing whether this was related to mutation or expression of the p53 gene. In both NMSC and bladder tumors we found a high prevalence of EMAST (75.4 and 43.9%). In NMSC the prevalence of EMAST was higher in tumors that had either p53 or ptch LOH, although the difference was not statistically significant. There was a significant association of extensive EMAST (three or more loci) with mutations in p53 among the bladder cancer tumors, but no indication of elevated EMAST in tumors with abnormal p53 staining without mutation. The association of EMAST with p53 mutation was confined to non-invasive disease. Hence, EMAST likely reflects a particular pattern of somatic events that are interactive with p53 mutation, particularly common in skin cancer and limited to non-invasive disease in bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Microsatellite instability at tetranucleotide repeats in skin and bladder cancer

et al. 2002

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“…Epidemiological data (5,6,8,9,(11)(12)(13)(14)(15)(16) show clearly that ultraviolet (UV) radiation, particularly UVB, is an essential etiological factor in the carcinogenesis of skin tumors. UV exposure is a chronic oxidative stress (17) that causes DNA damage with specific mutations of suppressor genes such as p53 (14,16,(18)(19)(20)(21)(22): it is activated along with telomerase (23)(24)(25)(26)(27). Molecular changes in the skin are associated with local cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Fabricius

Kruse-Boitschenko²,

Khoury³

et al. 2009

Int J Oncol

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Abstract.In previous studies we demonstrated telomerase activity in frozen tissues from BCC and their tumor-free margins by the PCR ELISA. In this study we examined in the same frozen sections immunohistochemical presence of hTERT in the nucleus. After fixation in acetone and methanol followed by steaming we used for visualization the antigenantibody reactions by APAAP. This was the best method of preparation of the frozen sections in our preliminary hTERT-study with squamous cell carcinomas. This study was supplemented with antibodies against Ki-67, nucleolin, common leucocyte antigen CD45 and mutated p53. The immunoreactive scores were determined and included the comparison with telomerase activity. The investigation of hTERT expression was performed in the tissues of 41 patients with BCC and control tissues of 14 patients without tumor. Eleven commercial antibodies were used for a nuclear staining of hTERT expression. With the anti-hTERT antibodies we looked for both satisfactory distribution and intensity of immunohistochemical labeling in the carcinomas and in the squamous epithelia of the tumor centers, of the tumor-free margins and of the control tissues. The hTERT expression in the BCC was distributed heterogeneously. The score values established by the anti-hTERT antibodies used were variably or significantly increased. In the stroma they tended to be negative, so we disregarded stroma hTERT. Proof of hTERT did not differ uniformly from telomerase activity. We compared the high with the lower median hTERT values in the Kaplan-Meier curve. Patients with lower hTERT scores in the center or tumor margin as shown by some of the antibodies suffered relapse earlier. Finally, we compared the hTERT expression in BCC tissues with the hTERT scores in HNSCC tissues from our previous study. Only one anti-hTERT antibody (our Ab 7) yielded significantly higher scores in BCC than in HNSCC.

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“…There are many reasons to link abnormalities in p53 signaling with development of UV-light responses, with an obvious relationship to skin cancer. First, it was demonstrated early on that precancerous human skin lesions, and later invasive skin cancers, frequently harbored p53 mutations bearing UV-light induced mutation signatures (Brash et al, 1991;Nelson et al, 1994;Ouhtit et al, 1998;Bolshakov et al, 2003). Second, use of p53 null mice, or mice engineered to overexpress mutated p53 proteins, were found to display increased incidences of malignant progression and conversion (Kemp et al, 1993;Weinberg et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

et al. 2005

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Ultraviolet (UV) light exposure is a common cause of epithelial-derived skin cancers, and the epidermal response to UV-light has been extensively studied using both mouse models and cultured human keratinocytes (KCs). Elimination of cells with UV-induced DNA damage via apoptosis provides a powerful mechanism to minimize retention or expansion of genetically abnormal cells. This cell editing function has largely been ascribed to the biological role of the p53 tumor suppressor gene, as mutations or deletions involving p53 have been linked to skin cancer development. Rather than introducing mutations, or using cells with complete loss of wild-type p53, we used an siRNA-based approach to knockdown, but not eliminate, p53 levels in primary cultures of human KCs followed by UV-irradiation. Surprisingly, when p53 levels were reduced by 50-80% the apoptosis induced by exposure to UV-light was accelerated and markedly enhanced (two-to three-fold) compared to control siRNA treated KCs. The p53 siRNA treated KCs were characterized by elevated E2F-1 levels accompanied by accelerated elimination of the Mcl-1 and Bcl-x L antiapoptotic proteins, as well as enhanced Bax oligomerization. Forced overexpression of either Mcl-1 or Bcl-x L reduced the UV-light enhanced apoptotic response in p53 siRNA treated KCs. We conclude that p53 not only can provide proapoptotic signals but also regulates a survival pathway influencing Mcl-1 and Bcl-x L levels. This overlooked survival function of p53 may explain previous paradoxical responses noted by investigators using p53 heterozygous and knockout mouse models, and opens up the possibility that not all liaisons within the cell involving p53 necessarily represent fatal attractions.

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UV-Radiation-Specific p53 Mutation Frequency in Normal Skin as a Predictor of Risk of Basal Cell Carcinoma

Abstract: Our results indicate that tandem CC --> TT mutations involving codons 247 and 248 of the p53 gene are associated with an increased risk of BCC but cannot be used as an accurate measure of total UV-radiation exposure.

Cited by 81 publications

References 29 publications

Microsatellite instability at tetranucleotide repeats in skin and bladder cancer

Microsatellite instability at tetranucleotide repeats in skin and bladder cancer

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

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