Meningiomas are the most common tumors of the central nervous system, accounting for about 15% of all primary brain tumors [1]. This frequency increases with advancing age and is greater in women. The exact molecular pathogenetic mechanisms that lead to meningiomas in a stepwise process are poorly understood with relatively few genetic alterations being currently known. The most frequent genetic alteration detected in these tumors is loss of heterozygosity on chromosome 22q [1,2]. This finding led to the identification of the NF2 tumor suppressor gene on 22q12, that is frequently mutated in sporadic meningiomas [3]. About one-third of NF2 patients present with multiple meningiomas [1,4].

The NF2 gene product, merlin, is a member of the family of erythrocyte band 4.1 membrane-associated proteins [5]. Merlin is homologous with cytoskeleton-associated proteins and it probably functions as a membrane organizing protein. It binds to a number of cellular proteins (p165, p145, p125, p85 and p70) and is constitutively phosphorylated on serine and threonine residues [6]. However, its phosphorylation state does not appear to be modulated during cell stimulation by growth factors, and merlin may be involved in signaling growth inhibitory pathways [6]. Mutations in the NF2 gene with associated loss of merlin, give rise mainly to acoustic neuromas, Schwann cell-derived tumors and meningiomas, and also occur in some breast carcinomas and malignant mesotheliomas [1].

      Another pathway that controls cell growth and differentiation and is stimulated by growth factors, involves membrane-bound N-ras GTPase [7]. This pathway has not been connected to NF2-related cytoskeleton factors, but we and others have observed that some meningiomas contain mutant forms of the N-ras oncogene [8,9]. Normal p21 N-ras hydrolyzes GTP at a high rate, and exists in an equilibrium between an active (GTP-N-ras) and an inactive (GDP-N-ras) state. The rates of GDP release and GTP hydrolysis are increased by three classes of regulatory proteins: the GTPase-activating proteins (GAPs, such as neurofibromin, that is the product of the neurofibromatosis 1 gene), the guanine nucleotide-release proteins (GNRPs), and the guanine nucleotide-dissociation inhibitors (GDIs) [7]. Amino acid mutations at codons 12, 13, 59 or 61 of the N-ras gene result in highly oncogenic proteins that lack GTPase activity [10,11].

We are currently studying a series of meningiomas in order to detect any possible interaction of the N-ras and the NF2 pathways of cell growth control. We used two approaches, i.e., the immunohistochemical detection of normal N-ras, and a search for the most common mutations in hot spots of the NF2 gene. Here, we present preliminary evidence suggesting that the two pathways play an important role in oncogenetic steps towards malignancy of meningiomas.