Identification of molecular alterations in human meningiomas

Meningiomas represent one of the most common tumors of the central nervous system, comprising approximately 20% of intracranial and 25% of intraspinal neoplasms. However, the mechanisms underlying meningioma formation remain poorly understood. Cytogenetic and DNA studies of meningiomas have identified multiple genetic aberrations in these tumors, suggesting meningioma tumorigenesis may involve the functional inactivation of several, unknown genes. Because meningiomas are a frequent component of the inherited disorder Neurofibromatosis 2 (NF2), it has been hypothesized that the NF2 susceptibility locus may also be responsible for the formation of meningiomas. To assess the possible role of the NF2 gene in meningioma tumorigenesis, the status of this gene in sporadic meningiomas was analyzed. This analysis revealed that while the NF2 gene is mutated in some meningiomas, many meningiomas do not exhibit NF2 gene mutation. Thus, pathways other than those associated with mutation of the NF2 gene likely are involved in the formation of many meningiomas. Clues to the nature of pathways important to the formation of other tumor types have often been obtained by recognition of critical alterations in gene expression patterns. Therefore, the identification of genes whose expression is absent or altered in meningiomas may point to pathways important in meningioma tumorigenesis. To identify such genes, this study has utilized a subtractive hybridization strategy to generate a cDNA library enriched for expressed sequences that are altered in meningiomas. This approach has led not only to the identification of several cDNAs that are differentially expressed in meningiomas, but has also revealed the unexpected presence of widespread microsatellite alterations in meningiomas. Recently, the presence of such microsatellite instability has been attributed to defective DNA repair in certain tumors. These findings provide evidence that genomic instability, likely resulting from faulty DNA repair, represents a previously unrecognized pathway of meningioma tumorigenesis. Collectively, these studies have provided a better understanding of the molecular changes associated with meningioma tumorigenesis. They also provide the basis for studies to dissect the role of defective mismatch repair in meningioma tumorigenesis