Inherited Susceptibility Factors

In general, germline mutations and metabolic mutations (polymorphisms) are the two groups of genetic alterations that are associated with increased constitutional cancer risk. Both of these groups of inherited susceptibility factors have been implicated in meningioma development. The first group consists of genes that exhibit high penetrance but are present in a low frequency in human populations. The familial occurrence of meningiomas, usually multiple, occurs often in association with NF-2. Overall, more than 50% of NF-2 patients develop meningiomas. The phylogenetically conserved gene that is the target for NF-2 resides on chromosome 22q12 and was cloned in its entirety in 1993. Studies of both meningiomas from NF-2 patients and sporadically occurring menin-giomas firmly place the NF-2 tumor suppressor gene in a causal role for tumorigenesis of meningiomas. It was recently shown that NF-2-associated and sporadic meningiomas share a common spectrum and frequency of allelic losses and similar proliferative activity. The NF-2 gene encodes for a protein of 595 amino acids termed "schwannomin" or "merlin". Schwannomin/merlin is a member of the band 4.1 superfamily of proteins that are thought to play crucial roles in linking cell membrane proteins with cytoskeleton, a previously unknown site of activation of tumor suppressor genes in humans.

Werner's syndrome (WS) is one of several rare genetic disorders characterized by genetic instability and premature onset of age-related diseases, such as atherosclerosis and an unusual spectrum of tumors that includes soft-tissue sarcomas, thyroid cancers and meningiomas. The gene mutated in WS patients - WRN gene - encodes for a DNA helicase, an enzyme that helps DNA unwind [37]. The WRN gene appears to function as a key element in resolving aberrant DNA structures that arise from DNA metabolic processes, such as replication, recombination and/or DNA repair, to preserve the genetic integrity of cells. The role of WRN

gene product in tumorigenesis of WS-related and sporadic meningiomas, as well as in radiation-induced meningiomas, is unknown.

The second group of inherited susceptibility factors for meningioma consists of genes that exhibit low penetrance but appear in human populations with a high frequency. Glutathione S-transferase and cytochrome P450 are examples of genetic polymorphisms that affect the ability of the body to detoxify carcinogens, including those that can induce meningiomas in laboratory animals. Both GST-T1 null and P450 CYP2D6 poor metabolizer alleles are associated with a significantly elevated risk for menin-gioma development. Clearly, GST and P450 genes, as well as other polymorphic genes that are involved in the metabolism of carcinogenic compounds found in diet, cigarette smoke and some industrial chemicals, may be promising candidates to explain the gene-environment interactions in meningioma development.

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