Abstract
Basal cell carcinoma (BCC) is the most common cancer among Caucasians. It generally occurs on sun-exposed areas of the body, mostly on the head and neck (80%), trunk (15%), rarely on arms and legs. Basal cell carcinoma is a good example of a disease caused by a combination of genetic and environmental factors. Ultraviolet (UV) radiation plays a dual role in the development of BCC: it causes DNA damage and immunosuppression. UVA and UVB rays damage the DNA via various mechanisms. UVB radiation directly damages DNA within skin cells, causing cytosine → thymine mutations at dipyrimidine sites, whereas UVA radiation is 10.000 times less mutagenic, but it is significantly more present in the natural UV radiation. Also, UVA photons have lower energy than UVB photons and do not induce mutations. UV radiation exerts immune suppression by decreasing the antigen presenting cells ability and by producing immunosuppressive cytokines, such as interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α). Mediators of UV-induced immunosuppression are DNA and cis-urocanic acid. Several studies showed a significant association between the development of BCC and sun-exposure during childhood and adolescence, and a strong relation with family history of skin cancer. Exposure to ionizing radiation increases the risk of nonmelanoma skin cancers by three times, while the risk is proportional to the radiation dose. Chemical carcinogens, such as arsenic, tar, psoralen, and pesticides, increase risks for nonmelanoma skin cancers, predominantly for squamous cell carcinoma (SCC). Regarding genetic predisposition, there is glutathione S-transferase (GST) as an important part of cellular defense against endogenous and exogenous chemicals. Several polymorphisms in GST family members have been associated with impaired detoxification, thus influencing the risk for some cancers, including nonmelanoma skin cancers. Cytochrome P450 enzymes are involved in detoxification of photosensitizing agents, and thus involved in BCC carcinogenesis. PTCH is a tumor suppressor gene first identified in patients with Gorlin syndrome. Abnormal activation of this gene and its pathways result in various types of tumorigenesis. BCC is associated with homozygous PTCH gene deletion. With regard to acquired genetic mutations, it was found that aggressive BCCs are significantly associated with increased p53 protein expression, probably representing the mutated form, although that assertion could not be established with certainty. Considering the apparently limited contribution of DNA damage and chromosome instability to the expression of BCC phenotype, the relevance of p53 mutations for BCC growth remains to be demonstrated. Data on the role of Bcl-2 gene family in the development of BCC are scarce. It is unclear whether Bcl-2 has a functional role in the development of BCC, or it only indicates the level of gene expression in tumor stem cells. Activation of Ras gene may play an important role during early stages in the development of nonmelanoma skin cancers, and it is often found on UV-exposed skin in BCC, actinic keratosis and SCC. Concerning immunologic factors, studies have shown that tumor necrosis factor-α (TNF-α) is the critical mast cell product involved in ultraviolet-induced immunosuppression: mast cells contain high quantities of TNF-α which is released after activation; the level of TNF-α is increased in the skin exposed to UV radiation disrupting the morphology and function of Langerhans cells, the principal antigen-presenting cells of the skin. An animal study suggests that the degree of susceptibility to ultraviolet-B-induced local immunosuppression depends on TNF-α level within the epidermis after UVB. It has been established that mast cell-derived histamine stimulates prostaglandin E2 (PGE2) production from keratinocytes. PGE2 alters the cytokine balance in favor of the immunosuppressive interleukin-10 (IL-10) against the immunostimulatory IL-12; histamine also increases suppressor T-cell function by binding to the H2 receptors, which in turn release higher levels of immune suppressive cytokines including IL-10 and induce apoptosis of antigen-presenting cells. All this results in a shift of the immune response from T helper 1 (Th1) cytokine profile to T helper 2 (Th2) cytokine profile, inhibiting antigen-presenting cells to induce antitumor activity.
UV-Radiation-Specific p53 Mutation Frequency in Normal Skin as a Predictor of Risk of Basal Cell Carcinoma
