This project seeks to provide insight into the poorly understood molecular pathogenesis of keratoacanthomas and skin adnexal tumors. To do so, it will exploit our currently more well-developed understanding of colorectal neoplasia. In particular, stabilizing mutations in beta-catenin and microsatellite instability (MSI) are two prominent aspects of colorectal neoplasia that recently been linked to skin tumors by study of transgenetic animals and preliminary studies of human tumors. The presence of beta-catenin mutations will be documented in keratoacanthomas and selected follicular adnexal tumors using immunohistochemistry for nuclear localization of the beta-catenin molecules and subsequent documentation of mutations in the CTNNB1 genes that encode this protein. This will be accomplished using paraffin- embedded human tumors from archived pathology diagnostic material. Examination of mutations in beta catenin in follicular adnexal tumors will provide information concerning the classification of these tumors. Combining the mutational analysis with clinical follow-up will provide insight into their biological behavior and potential. Certain sebaceous skin adnexal are markers for the Muir-Torre syndrome. The study of microsatellite instability (MSI) through the benign to malignant spectrum of these neoplasms will establish where MSI plays a substantial role in sporadic sebaceous adnexal neoplasms and will define more specifically which tumors are likely to be linked to the Muir-Torre syndrome than is currently possible with histological examination alone. Earlier detection of patients with Muir-Torre would allow for more timely aggressive screening for internal malignancies. In addition, since most sebaceous neoplasms are not linked with the rare-Muir-Torre syndrome, the ability to exclude this syndrome when the characteristic lesions are present could prevent unnecessary aggressive screening. Study of the frameshift mutations in selected genes with repetitive nucleotide sequences (microsatellites) will extend our understanding of mutational effects of MSI to skin adnexal tumors and keratoacanthomas that will inform our understanding of their pathogenesis, clinical behavior, treatment, classification, and biological potential.
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