Unraveling the human genome has lead to rapid advances in our knowledge of the molecular genetic controls that regulate and determine both normal and pathological tissue development. While progress has been rapid and substantial in the areas of simple hereditary conditions, far less has been learned of complex conditions including the molecular events leading to and driving tumorigenesis. The development of molecular biological techniques that allow analysis of large numbers of genes simultaneously now makes it possible to effectively and efficiently evaluate gene expression between different tissues and/or neoplasms. These powerful molecular techniques allow novel experimentation into the relationship between the phenotype and genotype of both normal and pathological tissues. Previous studies show overexpression of and/or mutation of RAS genes in odontogenic tumors and the genesis of tumors in locations where stem cells are localized. We hypothesize that the heterogeneous odontogenic tumor phenotypes result from differential expression of multiple genes that are downstream of the RAS and/or WNT pathways. We propose to test this hypotheses by ascertaining odontogenic tumors from humans having phenotypically diverse lesions including ameloblastomas, odontomas, odontogenic keratocysts and less common tumor types. Detailed phenotype profiles will be determined on all tumors using clinical, histological, and imaging techniques. Characterization of differential gene expression between tumors will be accomplished using cDNA microarrays printed to evaluate 16,000 mouse or human genes. Differential gene expression of specific cell populations within tumors will be evaluated using Laser Capture Microscopy and microarrays. RAS and p53 genes will be sequenced for mutations to discover molecular initiators of tumorigenesis. Microarray data is analyzed using state of the art bioinformatics to identify over and underexpressed genes compared with a commercially available reference RNA that allows standardization between laboratories conducting similar research. Gene data will be placed on our web site in a timely fashion for data sharing. These studies will provide the first detailed mutational and gene profile studies of human odontogenic tumors.
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