Neurofibromas, present in nearly all NF1 patients, can cause disfigurement or disability and can develop into lethal malignant tumors. In NF2 patients, benign schwannomas develop due to mutations in the NF2 gene, either sporadically or subsequent to mutations in schwannomatosis genes, and rarely transform. Factors causing neurofibroma and schwannoma formation are largely unknown. It is also not known whether there are common biological pathways that underlie formation of all types of peripheral nerve tumors. To understand how tumors form and to ultimately halt their formation, we are bringing together these investigators to compare and contrast human NF1, NF2, and schwannomatosis tumor data. Research into the role of specific genes in tumors was previously restricted to identification of changes one by one. It is simplistic to believe that complex processes such as tumor formation are mediated through single changes. Technologic advances have made possible a comprehensive understanding of complex biological processes at the cellular level. First, detailed DNA databases have resulted from genome sequencing. Second, high density "arrays" of individual DNA segments can be placed onto solid supports and used to compare the expression of tens of thousands of genes among many samples. Using this method of high-throughput microarray analysis of mRNA and functional genomics, we previously identified 138 genes and proteins that are implicated in neurofibroma formation. The genes identified as differentially expressed are now targets for further study. Here we plan to extend our high throughput functional genomics effort to NF2 and schwannomatosis and to test in cell culture assays if the identified differentially expressed genes are relevant to tumorigenesis in NF1, NF2, or schwannomatosis. The huge amount of data generated in comparisons of normal and NF1, NF2, and schwannomatosis-mutant cells is far beyond the capacity of any single lab to study in detail. Therefore, it is crucial to develop a system that allows sophisticated data analysis and data sharing across laboratories. An important aim of this proposal is to coordinate laboratories to generate and share data and to make the data available to the scientific community at large. To accomplish this, we are working with a functional genomics facility to mine the data. Data mining uses sophisticated computer programs to compare large data sets, so that gene expression patterns unique or common to neurofibroma and schwannoma cells can be identified. We anticipate gaining novel and important insights into the undoubtedly complex molecular and cellular mechanisms by which peripheral nerve tumors develop, thus providing molecular targets for future therapeutic approaches.