Malignant melanoma is an important public health concern, showing an alarming, recent increase in incidence. Although excessive exposure to ultraviolet (UV) radiation in sunlight is believed to be important, the precise role of UV in melanomagenesis is poorly understood. Photocarcinogenesis is a complex, multistage process with both genetic and environmental determinants. The relationship between excessive sunlight exposure and melanoma incidence is not simple, and heredity can be a strong predisposing factor. To increase ones understanding of mealanomagenesis in the human population, it is critical to develop and test hypothesis which attempt to correlate the dynamics of sunlight exposure with genetic factors controlling melanoma susceptibility. TO accomplish this goal, there is a need for animal melanoma models in which genetic components can be easily recognized and potentially isolated. A unique, nonmammalian vertebrate animal model for melanomagenesis is available in genetic hybrids of the genus Xiphophorus, in which genetic factors can be manipulated through genetic hybridization of different Xiphophorus species. Recently, UV-inducible Xiphophorus melanoma models have been developed. The long term goal of this research project is to identify functional genetic elements important in UV carcinogenesis leading to melanoma formation. To accomplish this goal, Xiphophorus genetic hybrids will be used in UV carcinogenesis protocols and melanoma susceptibility factors will be identified by genetic analyses. DNA from tumors will be examined for alterations in known tumor suppressor genes, and the expression levels of tyrosine kinases (Xmrks) known to be important in melanomagenesis in Xiphophorus will be analyzed directly in tumor samples. New genetic hybrid models will be produced and tested for susceptibility to UV carcinogenesis, and the effects of homozygosity for a tumor suppressor gene known to be important in these tumor models, DIFF, will be investigated in several Xiphophorus hybrid models. To enable robust genetic analyses, the Xiphophorus gene map will be expanded using polymorphic isozyme, RFLP, and arbitrarily-primed polymerase chain reaction (AP-PCR)-generated genetic markers, focusing on the detailed genetic and molecular characterization of the DIFF region in specific Xiphophorus crosses. Genetic markers for all of the 24 Xiphophorus chromosome pairs will be provided. These approaches will ultimately result in marker saturation for the DIFF region and provide an avenue to molecular cloning of the DIFF gene as well as other tumor susceptibility loci identified by genetic analysis.
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