A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma.

Abstract

Sunlight is a carcinogen to which everyone is exposed. Its UV component is the major epidemiologic risk factor for squamous cell carcinoma of the skin. Of the multiple steps in tumor progression, those that are sunlight-related would be revealed if they contained mutations specific to UV. In a series of New England and Swedish patients, we find that 14/24 (58%) of invasive squamous cell carcinomas of the skin contain mutations in the p53 tumor suppressor gene, each altering the amino acid sequence. Involvement of UV light in these p53 mutations is indicated by the presence in three of the tumors of a CC --TT double-base change, which is only known to be induced by UV. UV is also implicated by a UV-like occurrence of mutations exclusively at dipyrimidine sites, including a high frequency of C --T substitutions. p53 mutations in internal malignancies do not show these UVspecific mutations. The dipyrimidine specificity also implicates dipyrimidine photoproducts containing cytosine as oncogenic photoproducts. We believe these results identify a carcinogenrelated step in a gene involved in the subsequent human cancer.The frequency of skin cancers induced by sunlight in the United States approaches that of all other cancers combined and is doubling each decade (1-3). Ninety-five percent of these are non-melanoma skin cancers, resulting in one-third as many deaths as melanoma (4).Epidemiology has identified causal agents for many human cancers, including skin cancer (5), and reagents such as retroviruses have revealed genes that become oncogenic when mutated (6). Yet, the events between a human carcinogen and the human tumor mutations are unknown. Several questions central to oncology converge on these missing events. In the case of squamous cell carcinoma of the skin, they include the wavelength oflight, the gene that absorbs the photon, the DNA photoproduct, the contribution of mutagenesis versus systemic effects of sunlight such as immunosuppression, the type of mutation, possible hotspot sequences, and confidence that the genetic alterations observed in a tumor participated in tumor formation.Squamous cell carcinoma of the skin is an ideal cancer for determining which of the multiple steps in tumorigenesis are carcinogen-related for the following reasons.(i) The carcinogen is known; in lightly pigmented individuals of all races, the majority of skin cancers are due to sunlight. Of these, squamous cell carcinoma is more sunlightdependent than basal cell carcinoma or melanoma (1, 7). This carcinogen is physically well-defined, whereas agents such as tobacco smoke are complex mixtures.(ii) UV light produces distinctive mutations, leaving a "signature" in the DNA. Mutations due to direct absorption of UV light by DNA are predominantly C --T transitions at dipyrimidine sites, including CC --TT double-base mutations, in organisms from viral to human (refs. 8-12 and references therein). Because CC -* TT base changes are only known to be caused by UV, their presence identifies UV as the mutagen. The appearance of C...

A meta-analysis of the randomized controlled trials on elective neck dissection versus therapeutic neck dissection in oral cavity cancers with clinically node-negative neck

“…The p53 gene, located on chromosome 17p, is one of the most intensely studied tumor suppressor genes and its abnormality has been reportedly associated with the development of head and neck squamous cell carcinoma [14,51,93,114,129]. Its mechanism of action differs from the viral-induced carcinogenesis model in that it is the loss of one or both alleles of a tumor suppressor gene that induces cancer growth rather than the activation of proto-oncogenes.…”

p53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomarivus status

“…Epidemiological data have long implicated sun exposure as a risk factor for sporadic NMSC (Blum, 1948) and the recent demonstration of p53 mutations consistent with u.v. -induced damage in these tumours provides compelling molecular evidence to support this (Brash et al, 1991;Zeigler et al, 1993;Nataraj et al, 1995). Furthermore, the majority of skin cancers in immune suppressed transplant patients also occur on sun-exposed sites, but the role, if any of UVR in this group of patients has not been determined.…”

p53 alone or in combination with antisense cyclin D1 induces apoptosis and reduces tumor size in human melanoma

“…Ultraviolet light ( UV ) present in sunlight, especially UV within the B spectrum (29 -to 320 -nm wavelength ) has been implicated as a possible cause for melanoma development. UVB induces characteristic C!T and CC!TT mutations in the p53 gene, 2 and these mutations are seen in both primary melanomas and melanoma cell lines. 3,4 Although the exact role of p53 in the development of melanoma has been questioned, 5 the association between UV radiation and melanoma is clear.…”

“…We had three hypotheses: (1 ) intratumoral wt p53 monotherapy would lead to the shrinkage of preformed melanomas, (2 ) therapies that target different points in the cell cycle would be more effective than monotherapy, and treatment response would be prolonged, and ( 3 ) doubling the dose or repeat doses of p53 or AS CD1 would be more efficacious than a given dose of monotherapy. To test our hypotheses, we evaluated adenoviral vectors containing wt p53 and AS CD1.…”