The Etiology of UV-Induced Melanoma

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DESCRIPTION (provided by applicant): In contrast to sunlight-induced squamous cell carcinoma (SCC) the etiology of cutaneous malignant melanoma (CMM) is not well understood. In particular, the role that sunlight exposure and DNA damage play in the initiation of CMM is an open question. Early carcinogenesis studies by Richard Setlow using the Xiphophorus backcross hybrid model indicated that direct DNA damage caused by exposure to the DVB component of sunlight is necessary and sufficient for melanoma formation. Subsequent studies by Setlow showed that monochromatic UVA radiation that is not directly absorbed by DNA was also sufficient for melanoma induction in Xiphophorus. These results had significant public health consequences, suggesting that although sunscreen use may inhibit UVB-induced erythema it may actually increase exposure to the UVA wavelengths that cause melanoma. An intensive worldwide public debate on sunscreen use and "abuse" ensued that is still engaged today. Consequently, there persists a perception among many laymen and scientists that CMM is primarily caused by free radical mechanisms associated with UVA rather than by damage resulting from direct absorption of UVB by DNA. Our data do not support a major role of free radical chemistry in melanoma induction. To the contrary, we believe that the direct damage caused by the absorption of UVB wavelengths by DNA (e.g., the cyclobutane pyrimidine dimer or CPD) is required for CMM formation and that the ability to repair these lesions plays a significant role in tumor susceptibility. The specific aims of this project are designed to test these ideas by examining (1) the wavelength- and DNA damage-dependence of melanoma formation in susceptible Xiphophorus backcross hybrid fish, (2) the genetic diversity and inheritance of nucleotide excision repair in Xiphophorus, and (3) gene expression and its modulation by UV in a melanoma susceptible hybrid model. From these studies we hope to define the effective solar wavelength boundaries of melanoma, identify the class of DNA damage critical to CMM and elucidate the role of DNA repair in tumor suppression.