The long-term objective of this proposal is to investigate the cellular and molecular basis for the genetic predisposition to skin cancer of individuals with BCNS. However, the current proposal deals solely with cellular aspects, although future studies on molecular aspects are anticipated. BCNS is an autosomal dominant genetic disorder in which the afflicted individuals are predisposed to multiple basal cell nevi and basal cell carcinomas. Preliminary studies have indicated that skin fibroblasts from BCNS individuals are hypersensitive to killing by UV-B/A (280-400 nm), but not UV-C (254 nm) radiation, compared to skin fibroblasts from normal individuals. However, the excision repair of UV-B/A-induced pyrimidine dimers was similar in BCNS and normal human skin fibroblasts. These results suggest that the increased sensitivity of BCNS skin fibroblasts to killing by UV-B/A radiation is not due to a defect in the excision repair of pyrimidine dimers, but due to a defect in some other repair mechanism involving either pyrimidine dimers or other, as yet, unidentified photoproducts. The fact that UV-B radiation present in sunlight is known to be responsible for the induction of most human skin cancers, together with the investigators' observation that BCNS cells are hypersensitive to killing by UV-B/A radiation, lend credence to the hypothesis that there may be an association between hypersensitivity to killing by UV-B/A radiation and genetic predisposition of individuals with BCNS to sunlight-induced skin cancers.
The specific aims of this proposal are: (1) To measure the sensitivity (in terms of survival) of BCNS and normal human skin fibroblasts and epidermal cells to broad-band UV-B/A, UV-A, and monochromatic (297 nm, 302 nm, 313 nm, 334 nm, or 365 nm) radiations; and (2) to examine the repair kinetics of UV-induced DNA damage in skin fibroblasts and epidermal cells from BCNS and normal individuals. Cell survival will be assayed by colony forming ability. The repair of pyrimidine dimers, (6-4) photoproducts and single-strand breaks in the DNA will be measured at various times during the post-UV recovery phase. The applicants state that an important aspect of this revised application is to determine whether the epidermal cells from BCNS patients also exhibit increased UV sensitivity and similar repair defect(s) as skin fibroblasts. The experiments using epidermal cells, they insist, are highly relevant because most skin cancers that arise in BCNS patients are epidermal in origin. Studies addressing these questions may lead to the identification of some of the defects that are associated with the pathogenesis of skin cancer in BCNS patients.
