Squamous cell carcinoma (SCC) of the skin is one of the most prevalent carcinomas and exhibits a dramatic rise in incidence with advancing age in human. A number of genes have been identified that are capable of driving SSC genesis, but little is known about the basis for the age-dependent increase in SCC incidence as well as the mechanisms driving the dramatically altered cytogenetic profiles - so-called chromosomal instability pattern. Recent studies in the telomerase knockout mouse have revealed that age-dependent telomere attrition (as a function of epithelial renewal) leads to telomere dysfunction that precipitates fusion-bridge-breakage cycles that lead to gains/losses in genetic information, resulting is cells with pro-cancer genotypes. Importantly, these mouse SSCs occur spontaneously with advancing age and possess cytogenetic profiles that are classical for human SCCs. These genetic studies point to telomere dysfunction as a major mechanism driving epithelial carcinogenesis and its associated chromosomal instability. In this proposal, we plan to exploit this novel carcinoma model and array-based comparative genomic hybridization methodology to begin to define the chromosomal aberrations that drive these cancers. These aberrations will be correlated with the biological features of the cancer including latency, invasiveness and histological grades.
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