There are two main types of skin cancer: melanoma, arising from the neural crest derived melanocytes; and basal cell carcinoma and squa-mous cell carcinoma derived from keratinocytes (the latter two referred to as non-melanoma skin cancer, NMSC) (Rees, 2002b). This broad distinction into two types is useful: NMSC is extremely common and case-fatality extremely low (<0.5%); melanoma by contrast is less common but with a case fatality of -20% (Rees, 1998).
Melanomas usually present as pigmented lesions with a darkening and increase in size of a preexisting melanocytic nevus (a benign collection of immature melanocytes) or de novo, as a lesion resembling a mole that is growing and getting darker. Melanoma may metastasize early and fatality is usually due to secondary spread. Because therapy of the tumor once spread has occurred is largely palliative, emphasis has been on primary prevention, early detection and excision of malignant lesions, and identification of high risk groups (Rees, 1998).
Basal cell and squamous cell cancers are keratinocyte-derived tumors that usually present as skin-colored and scaly or crusted lesions on sun-exposed sites. They are rarely fatal. Basal cell carcinomas rarely metastasize, and in 99% of cases can be easily treated using either destructive surgical approaches or more recently pharmacological agents topically applied. Squamous cell carcinomas of the skin can metas-tasize and are usually treated by excision with or without radiotherapy. Their biological behaviour and clinical impact is far less than for other keratinocyte derived tumors on non sun exposed sites such as the cervix or the oral mucosa.
The main environmental determinant of both melanoma and NMSC is ultraviolet radiation (UVR) exposure (although since the body-site distribution and age incidence of the various tumor types differs, the exact relation between the pattern of UVR exposure and tumor incidence, or other host factors, are also likely to be important). The main genetic determinant of skin cancer is the presence or absence of a susceptible phenotype, the main determinant of a susceptible phenotype being the degree of melanin pigmentation of the skin. The genetics of skin cancer, at least on a global scale, is therefore in large part the genetics of human pigmentation.
The color of skin is principally due to the presence of the two main chromophores: melanin and hemoglobin. Differences in skin colour between people (in the resting state) are chiefly due to differences in the amount of melanin produced by melanocytes.
Melanin is a complex mixture of polymers of at least two main classes. Eumelanins are brown or black nitrogenous pigments, insoluble in all solvents, which arise by oxidative polymerization of 5,6 dihydroxyindoles derived from tyrosine via dopaquinone. Pheomelanins are alkali soluble, yellow to red pigments, contain sulphur in addition to nitrogen, and arise by oxidative polymerization of cysteinyldopas via benzothiazine intermediates (Prota et al., 1998). A number of gene products have been identified as being involved in the biosynthesis of melanin including tyrosinase and a family of tyrosinase-related proteins.
Melanin strongly absorbs electromagnetic radiation across both the visible and ultraviolet spectrum. Maximum absorption is in the shorter wavelengths where DNA damage from UVR is maximal. Melanin is produced within endosome-like structures (melanosomes) within melanocytes and passed to neighbouring keratinocytes. Simple histological staining of keratinocytes show little crescents of melanin on top on the nuclei of keratinocytes, particularly in the basal layer of the epidermis. The importance of melanin in protecting against skin cancer is illustrated by the relative absence of most skin cancer in many African populations, and the dramatically raised rates in those who are unable to synthesis melanin in adequate quantities (albinism (Lookingbill et al., 1995)).
Skin pigmentation due to melanin is a highly heritable trait, and skin color was once used to determine the zygosity of twins. Twin studies of a sample of 134 Australian twins give a heritability of 0.83 for skin color measured at 685nm at the inner forearm (Clark et al., 1981). Values for more UVR-exposed sites such as the forehead are much lower and can be accounted for purely by environmental factors. This initially surprising result reflects large variation in UVR exposure and needs to be taken in context. Pigmentation is of two sorts: constitutive and facultative, the former referring to colour in the absence of UVR and the latter, color in response to UVR. In practice, the upper inner forearm receives UVR (as does even the buttock, a site that is to be preferred in such studies) and it seems likely that the figure quoted of 0.83 is likely to be an underestimate. Similarly, the lower heritability quoted for sun-exposed skin needs to be interpreted in the light of high ambient exposures in Australia, and the limited range of skin colors examined. A study of a more diverse genetic group would by definition decrease the environmental influence.
Study of coat colour mutations in the mouse fancy communities has identified a large number of genes important in coat and skin color (Barsh, 1996; Jackson, 1997). Interference with pigmentation can be due to a number of different processes being affected: failure of successful migration of melanocytes to the skin; inadequate biosynthesis of the melanin polymer; or inadequate packaging and transfer of the mature melanosome into the surrounding keratinocyte. Many of the mutations that have been discovered underpin these varied processes (Barsh, 1996; Jackson, 1997).
Although a large number of loci underlying rare Mendelian disorders in man have been identified following previous work in the mouse, until recently and with one exception, the melanocortin 1 receptor (MC1R), the importance of these loci to normal physiological variation in pigmentation in man has been unclear. Studies not yet published (Brilliant, M. personal communication) however suggest that many SNPs in, or close to, loci implicated in coat color mutants in mouse influence human pigmentation. Additionally, following the elucidation of the genetic basis of the golden mutant in zebrafish, the human homolog, SLC24A5, appears to be a key determinant of physiological pigmentary variation in man (Lamason et al., 2005). In the section below I discuss in detail what we have learned of the relation between allelic variation at the MC1R and human pigmentary phenotypes. However, it is likely that within several years the majority of normal skin and hair colour variation in man will be accounted for in terms of loci that have already been identified.
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Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.