DNA REPAIR AND CHROMOSOME INSTABILITY IN SKIN CANCERS

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Basal cell and squamous cell carcinomas (BCC and SCC) commonly occur on exposed sites such as the head and neck and are usually due to chronic exposure to solar ultraviolet radiations (UVR). The role of host susceptibility to UVR carcinogenesis is not well defined at either the molecular or cytogenetic level. We propose to conduct a case- control study to evaluate the association between genetic susceptibility to UVR (defined as decreased DNA repair capacity or increased mutagen sensitivity) and the development and progression of skin carcinomas. The DNA repair capacity will be measured by host-cell reactivation assay with UV- irradiated plasmids. Mutagen sensitivity will be measured by UVR induced chromosomal breaks and the frequency of break sites on chromosomes. We will use peripheral blood lymphocytes from 300 untreated cases (150 BCC and 150 SCC) and 300 controls to perform these assays. The specific aims of this proposal are: (1) to examine the association between DNA repair capacity and the development of skin carcinomas, (2) to examine the association between mutagen sensitivity and athe development of skin carcinomas, and (3). To examine the association between the frequency of break sites on chromosomes and the development and progression of skin carcinomas, and (4) to evaluate the association of DNA repair capacity with mutagen sensitivity, frequency of chromosomal break sites, gene mutations, and epidemiologic and clinical variables such as sunlight exposure history, clinical stage of disease, and treatment outcomes. We will investigate the relationship between these two genetic susceptibility markers and the development of skin carcinomas in relation to phenotypic characters, family history, sunlight and other carcinogenic exposures, the frequency of mutations in ras oncogenes and p53 tumor suppressor genes clinical stage and progression of tumors (to be collected by Core B; Drs. Margaret Spitz, Randal Weber, and Honnavara Ananthaswamy) and treatment outcomes (to be measured by Drs. Scott Lippman and Reuben Lotan) from the same subjects. This study will provide information regarding the utility of these markers of genetic susceptibility in identifying individuals at high risk of developing skin carcinomas.