RISK ASSESSMENT OF DNA REPAIR HETEROGENEITY IN HUMANS

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The ubiquitous environmental gentoxicant, ultraviolet light (UV), produces DNA damage, which if left unrepaired, can give rise to several biological effects including cell death, mutations and cancer. The human disease, xeroderma pigmentosum, exemplifies how reduced DNA repair capacity can lead to a higher incidence of cell lethality, higher mutation frequencies and a predisposition to cancer. The repair of UV-induced DNA damage is achieved by a complex interaction of >10 different gene products in a process called nucleotide excision repair. There is increasing evidence that DNA repair capacity, like any phenotypic trait, is heterogeneously distributed among the human population. Therefore certain individuals within the human population with low DNA repair capacity may be more prone to the adverse biological effects of environmental genotoxic agents, such as UV light. The goal of this study is to validate and apply within the human population several biomarkers of exposure and susceptibility to the environmental mutagen, ultraviolet light. In order to achieve this goal we will examine DNA repair capacity, cytotoxicity, and mutation frequency in peripheral lymphocytes of patients with skin cancer. More specifically the patient cohorts will be defined by the presence of one or more basal cell or squamous cell carcinomas and will be stratified into three age groups: l) less than 40 years old, 2) 40-50 years old, and 3) greater than 50 years old. Two major age-independent subgroups will be those patients with multiple skin cancers (MSC), (6 or greater) and patients with site clustering of skin cancers at specific body surfaces. All patients will be paired to age/sex-matched controls. We will test the hypothesis that low DNA repair capacity and high in vivo mutant frequency will correlate with increased risk of skin cancer using two DNA repair assays (SA1&2), a cytotoxicity assay (SA3) and an assay which measures the in vivo mutant frequency in a somatic gene (hypoxanthine phosphoribosyl transferase, HPRT) (SA4). Finally, in vitro studies of repair in isolated mutant clones will define the intra-individual interclonal heterogeneity of susceptibility to UV damage (SA6). The long-term goal of this study is to better understand the role of DNA repair in cancer susceptibility.