p53 mutation and cancer
p53 MUTATIONS IN SKIN CANCER
Basal cell carcinoma is the most common form of skin cancer. The second most common type of skin malignancy is squamous cell carcinoma. Although these 2 types of skin cancer are the most common of all malignancies, they account for less than 0.1% of patient deaths due to cancer. Both of these types of skin cancer are more likely to occur in individuals of light complexion who have had significant exposure to sunlight, and both types of skin cancers are more common in the southern latitudes of the Northern hemisphere. The overall cure rate for both types of skin cancer is directly related to the stage of the disease and the type of treatment employed. However, since neither basal cell carcinoma nor squamous cell carcinoma of the skin are reportable diseases, precise 5-year cure rates are not known. Although basal cell carcinoma and squamous cell carcinoma are by far the most frequent types of skin tumors, the skin can also be the site of a large variety of malignant neoplasms. These other types of malignant disease include malignant melanoma, cutaneous T-cell lymphomas (mycosis fungoides), Kaposi's sarcoma, extramammary Paget's disease, apocrine carcinoma of the skin, and metastatic malignancies from various primary sites
Basal cell carcinoma and squamous cell carcinoma are both of epithelial origin. They are usually diagnosed on the basis of routine histopathology. Squamous cell carcinoma is graded 1 to 4 based on the proportion of differentiating cells present, the degree of atypicality of tumor cells, and the depth of tumor penetration. Apocrine carcinomas, which are rare, are associated with an indolent course and usually arise in the axilla.
Basal cell carcinoma
Basal cell carcinoma is at least 3 times more common than squamous cell carcinoma in nonimmunocompromised patients. It usually occurs on sun exposed areas of skin, and the nose is the most frequent site. Although there are many different clinical presentations for basal cell carcinoma, the most characteristic type is the asymptomatic nodular or nodular ulcerative lesion that is elevated from the surrounding skin and has a pearly quality and contains telangiectatic vessels. It is recognized that basal cell carcinoma has a tendency to be locally destructive. High-risk areas for tumor recurrence include the central face (periorbital region, eyelids, nasolabial fold, nose-cheek angle), postauricular region, pinna, ear canal, forehead, and scalp. A specific subtype of basal cell carcinoma is the morphea-form type. It typically appears as a scar-like, firm plaque and because of indistinct clinical tumor margins, it is difficult to treat adequately with traditional treatments.
Squamous cell carcinoma
Squamous cell tumors also tend to occur on sun-exposed portions of the skin such as the ears, lower lip, and dorsa of the hand. However, squamous cell carcinomas that arise in areas of non-sun-exposed skin or that originate de novo on areas of sun-exposed skin are prognostically worse since they have a greater tendency to metastasize. Chronic sun damage, sites of prior burns, arsenic exposure, chronic cutaneous inflammation as seen in long standing skin ulcers, and sites of previous x-ray therapy are predisposed to the development of squamous cell carcinoma.
Actinic keratoses are potential precursors of squamous cell carcinoma. These typical red scaly patches usually arise on areas of chronically sun-exposed skin, and are likely to be found on the face and dorsal aspects of the hand. Although the vast majority of actinic keratoses do not become squamous cell carcinomas, it is thought that as many as 5% of actinic keratoses will evolve into this locally invasive carcinoma. Due to this premalignant potential, the destruction of actinic keratoses is advocated.
UV radiation-induced mutations have been studied in various animal models. The majority of the mutations are found to be located at dipyrimidine sites (i.e. (T-T, C-C, C-T or T-C) and correspond to a C to T transition. More than 20% correspond to tandem mutations involving the two adjacent nucleotides of the dipyrimidine sites (C-C to T-T).
Several human genetic syndromes are associated with DNA repair deficiency. Among them, xeroderma pigmentosum (XP) is an autosomal, recessively inherited disease. Patients with XP show clinical and cellular hypersensitivity to UV radiation, resulting in a very high incidence of skin cancer. In these subjects, the median age of onset of skin cancer is 8 years, nearly 50 years younger than in the general population.
Brash et al. showed that, in skin spinocellular cancer, C ---> T mutations predominate in pyrimidine dimers. It is well known that ultraviolet radiation, an etiological agent of most skin cancers, acts directly on these dimers. A particular characteristic of the action of UV radiation is the change in the bases CC ---> TT, observed in Brash's series but also in other skin cancer series such as basocellular cancers (Rady et al. 1992). In patients with genetic DNA repair deficiencies, such as xeroderma pigmentosum (XP), the phenotype is much more marked. All mutations found in skin cancers are located on the pyrimidine dimers and 55 % are tandem mutations CC ---> TT (Dumaz et al. 1994). This type of mutation is only very rarely found in internal cancers (less than 1 %). In skin cancers from XP patients, more than 95 % of the mutations are located on the noncoding strand of the p53 gene, while in other skin tumors and in internal cancers, no special trends are observed. This result therefore suggests that there is preferential repair of the coding strand, which has been confirmed by Toranaletti and Pfeifer, who showed that the repair rate of pyrimidine dimers in the p53 gene is highly variable, with an especially low rate in the codons that are often mutated in skin cancer. Such p53 mutations seem to be very early events as they can be found both in precancerous lesions such as actinic keratosis (Ziegler et al. 1994) and in normal skin exposed to UV (Jonason et al. 1996). Recent work have demonstrated that human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-neoplastic keratinocytes (Ponten et al. 1997; Ren et al. 1997; Ren et al. 1996; Ren et al. 1997; Ren et al. 1996).
These results taken together (predominance of CC -> TT lesions on the non coding strand) were experimentally confirmed in animals carrying UV-induced tumors (Dumaz et al. 1997; Kress et al. 1992).
Spectrum of p53 mutations in skin cancer