The rate of increase in the incidence of cutaneous melanoma is faster than that for any other cancer, especially in countries with large populations of fair-skinned Caucasians. These include the United States, Sweden, Canada, England, and particularly Australia, where it is considered to be at epidemic proportions (50/100,000). Melanoma is the 6th most common cancer for men and the 7th for women (4% of all cancer cases) in the United States. Although nonmelanoma skin cancers are, in general, not lethal, the health care costs for treating these skin cancers are considerable and likely to grow, estimated in 2001 to be about $650 million/year for the entire U.S. population. Skin cancers are also of concern to the military. A recent study of personnel who left combat zones in Iraq and Afghanistan between 2003 and 2006 for dermatologic reasons has identified the most common causes as: (1) dermatitis or general skin inflammation (20%); (2) benign melanocytic nevus (9%); and (3) malignant neoplasm (8%). Of particular concern is the finding that the individuals diagnosed as having malignant skin lesions were relatively young with median age of 42 years (range, 24-57 years). Their similarly deployed comrades are still likely to develop skin cancer later on in life because they were exposed to intense solar radiation, the major etiologic factor for basal cell carcinomas, squamous cell carcinoma, and melanomas.

Sun exposure in the context of individual's pigmentation characteristics is considered the main risk factor for skin cancers. It is usually assumed that the major reason is vulnerability to the mutagenic effects of ultraviolet light (UV) absorbed by DNA. However, the relationship of UV to melanoma is enigmatic. Melanoma patients frequently experienced intermittent severe sunburns during childhood and as young adults. Yet the long-time interval between sunburns and the appearance of melanoma suggests a progressive process in which unknown host factors and environmental exposures interact in a synergistic manner to cause a malignancy.

Our major goal is to address this conundrum by exploring the sun exposure-induced processes that lead to malignancy characteristic to pigment cells (melanocytes). We will study long-lasting sunlight-induced changes in the DNA of pigment cells having different predisposition genes. These changes may create a "cancer-positive" feedback loop that increases the cells' chance to become melanoma. Our studies are unique because we are incorporating the specific features of melanocytes, i.e., the pigmentary system, with UV-induced cellular reactions that include both direct DNA damage and production of reactive oxygen species, as well as the interplay between genetic and non-genetic inherited changes in the susceptibility to melanoma. We hypothesized that in melanocytes, reactive oxygen species are produced not only in response to ultraviolet irradiation, but also during the sunlight enhanced pigmentation process, overwhelming the defense mechanisms that normally exist against such radicals. For comprehensive analyses of sunlight-induced changes to DNA, we will employ state-of-the-art techniques that are currently becoming available at reasonable cost. Altogether, the studies are likely to show progressive, long-lasting changes in DNA that may explain the lengthy time interval between intermittent severe sunburn episodes and the onset of melanoma later on during adulthood.

Our studies are of translational nature because they will identify genetic markers and novel processes of carcinogenesis. The genetic markers can be used to identify individuals with excess risk of sunlight-induced melanoma. The novel malignant processes that we will discover may be amenable to manipulation and can be the basis for treatment plans that offset oncogenic insults of solar radiation. We will test anti-oxidants that effectively block sunlight-induced pro-cancerous events in melanocytes. Creams that incorporate anti-oxidants are already commercially available. In addition, drugs that prevent the non-genetic (termed "epigenetic") effects of sun exposure on DNA can also be anti-carcinogenic. Our studies may provide the impetus to use such creams and possibly to develop more effective ones. We expect that within three years, our research will accomplish these main translational endpoints.

Although our studies are focused on melanoma, they include normal and perilesional skin that may provide information relevant to non-melanoma skin cancers. Therefore, having markers that can predict skin cancer susceptibility may reduce the cost of treatment and human suffering.