Biology And Molecular Genetics

Significant progress has been made in the understanding of the biology and molecular genetics of meningiomas [1-3,20-22]. The tumors are thought to arise from malignant transformation of arachnoidal cap cells, which are meningothelial cells with both mesenchymal (e.g., spindle cell morphology, collagenous stroma) and epithelial (e.g., numerous intercellular junctions, expression of epithelial membrane antigen) features. Arachnoidal cap cells form the outer layer of the arachnoid mater and arachnoid villi, and have a diverse group of proposed functions. The most important functions include the formation of anatomic barriers and ensheathing of other cells and vessels, formation of conduits for CSF drainage into venous sinuses and veins, production of collagen and stromal proteins, secretion of CSF proteins and glioneuronal differentiation and proliferation factors, participation in foreign-body reactions, trophic support for glial and neuronal cells, and participation in reactive and reparative processes within the meninges [20,22]. In addition, arachnoidal cap cells perform other important duties such as intercellular communications via desmosomes, emperipolesis (i.e., lymphoplasmacytic engulfment), and HLA-DR expression.

Due to reports of familial clustering of meningio-mas and the increased incidence of meningiomas in patients with neurofibromatosis type 2 (NF2), many groups have begun to investigate the cytogenetic and molecular biological background of these tumors [1-3,20-22]. Recent reports would suggest that non-NF2-associated familial clustering of meningioma is rare, but does occur [23,24]. Several histological varieties of tumor have now been described that lack any association with NF2 or other genetic diseases. For patients with NF2, meningiomas are the second most common tumor, noted in approximately 50 per cent of the cases. Although children with meningiomas are generally uncommon, almost 40 per cent will have NF2. NF2-associated meningiomas differ from sporadic tumors in several ways, including a tendency to arise several decades earlier in life, to be multiple in most patients, and to belong to the fibroblastic variant. Meningiomas are also known to occur in other genetically mediated diseases, including Turcot's syndrome, Cowden's syndrome, Li-Fraumeni syndrome, Gorlin's nevoid basal cell syndrome, and von Hippel-Lindau disease.

Early cytogenetic studies of meningiomas documented numerous genetic alterations, including monosomy of chromosome 22 in up to 70 per cent of cases, as well as deletions of chromosomes 1p, 6q,

9p, 10q, 14q, and 18q [20-22,25,26]. Subsequent molecular studies have noted loss of heterozygosity on chromosome 22q as the most common genetic alteration, present in 40-70 per cent of all meningiomas. Further research has suggested that the NF2 gene is the usual target within 22q, with bi-allelic mutation or deletion of the gene occurring as an early event in the transformation process in 50-60 per cent of sporadic meningiomas and all NF2-associated meningiomas (see Fig. 34.1). The NF2 gene encodes the protein, merlin (also called schwannomin), which has an open reading frame of 595 amino acids, and is a member of the Protein 4.1 family. The 4.1 family are a group of structural proteins (including the ERM proteins ezrin, radixin, and moesin) that link the cytoskeleton to proteins of the cytoplasmic membrane. Merlin appears to play a role in the regulation of cell growth and motility through interaction with numerous proteins, including paxillin, b1-integrin, CD44, hepa-tocyte growth factor-regulated tyrosine kinase substrate, piI-spectrin, schwannomin interacting protein-1, and other ERM proteins [22]. Fibroblasts and keratinocytes that are deficient in NF2 exhibit increased proliferation and accelerated cellular movement in vitro. Genetically engineered mice (i.e., NF2 +/—) with reduced expression of NF2 have increased cell growth and develop a variety of invasive and highly metastatic tumors, including fibro-sarcoma, adenocarcinoma, hepatocellular carcinoma, and osteosarcoma [27]. Inactivation of NF2 in lepto-meningeal cells can lead to meningioma formation in mice [28]. If wild type merlin is re-expressed into

Meningioma WHO grade I Meningioma WHO grade I

FIGURE 34.1 Overview of the current molecular model of the stepwise pathogenesis from a normal arachnoidal cell to meningioma grades I, II, and III (solid lines and arrows). In some cases, there may be a more direct pathway from a precursor cell to a grade II or III tumor (dotted lines and arrows). Genetic alterations that may be involved in each step are listed and explained in the text.

Abbreviations: PR—progesterone receptors, WHO—World Health Organization, VEGF—vascular endothelial growth factor. Adapted from references [1,2,20-22]. See Plate 34.1 in Color Plate Section.

Meningioma WHO grade I Meningioma WHO grade I

FIGURE 34.1 Overview of the current molecular model of the stepwise pathogenesis from a normal arachnoidal cell to meningioma grades I, II, and III (solid lines and arrows). In some cases, there may be a more direct pathway from a precursor cell to a grade II or III tumor (dotted lines and arrows). Genetic alterations that may be involved in each step are listed and explained in the text.

Abbreviations: PR—progesterone receptors, WHO—World Health Organization, VEGF—vascular endothelial growth factor. Adapted from references [1,2,20-22]. See Plate 34.1 in Color Plate Section.

tumor cell lines, the cells have reduced growth and motility in vitro and in vivo [29].

The majority of meningiomas have absent or reduced immunoreactivity to merlin, which correlates strongly with loss of heterozygosity of 22q [20-22, 30-32]. This is consistent with the mutational spectrum of NF2 in meningiomas, since most mutations cause a truncation of the gene, with reduced or absent merlin expression. The frequency of NF2 mutations is variable among different histological varieties of meningioma [31]. It is most common in the fibroblastic and transitional forms, noted in 70-80 per cent of cases. In contrast, the mutation is only present in roughly 25 per cent of the cases with the meningothe-lial form. Immunohistochemical results are consistent with the mutational data, showing a lack of staining for merlin in fibroblastic and transitional meningiomas, but rarely in meningothelial tumors. There are some tumors with reduced or absent expression of NF2 that do not harbor mutations within the gene [32]. In these cases, it is possible that other mechanisms may be involved, such as homozygous deletions, methylation, or undetected NF2 mutations. The paucity of NF2 mutations in the meningothelial variant suggests that other transformation pathways are more important. NF2 mutations are present in sporadic patients with multiple meningiomas, but in tumors from familial clusters that have multiple tumors [33].

In addition to the NF2 gene, other genes have been implicated on chromosome 22, as well as on several other chromosomes [20-22]. Several candidate tumor suppressor genes located on 22q (e.g., ADTB1, RRP22, hSNF5/InI1, CLH-22) have been evaluated and found to have reduced expression in some cases. However, mutations within these genes have been infrequent in tumors with abnormal expression. Further research is needed to determine the role of these genes in the transformation of meningiomas. DAL-1 is a protein belonging to the 4.1 Family of membrane-associated proteins that has significant sequence homology with merlin [18]. It is a putative tumor suppressor gene and maps to chromosome 18p11.3. DAL-1 expression is reduced or absent in 76 per cent of sporadic meningi-omas, which is similar to merlin. Loss of DAL-1 expression also appears to be an early event in the pathogenesis of meningiomas, since the expression pattern was only slightly different between benign and atypical tumors (70-76 per cent) versus anaplastic tumors (87 per cent). Loss of heterozygosity of chromosomes 1, 14, and 10 are common in meningio-mas and tend to correlate with severity of grade [20-22,34]. Several putative tumor suppressor genes have been evaluated on chromosomes 1 (e.g., CDKN2C, RAD54L, ALPL, TP73) and 10 (e.g., PTEN,

DMBT1) for evidence of mutation, abnormal expression, or methylation. Thus far, none of these genes appears to play a significant role as a tumor suppressor in the pathogenesis of meningioma. In addition, no specific meningioma suppressor genes have been identified on chromosome 14. Chromosome 9 has been studied intensely due to the presence of several genes that are important for the regulation of the cell cycle and p53 (i.e., CDKN2A, p14ARF, CDKN2B) [35]. Recent reports suggest that the majority of malignant meningiomas (55-70 per cent) have mutations or expression abnormalities related to all three genes; these findings are significantly less frequent in benign meningiomas.

The expression of growth factors and their receptors have also been studied in meningiomas [20-22]. Several groups have provided evidence for paracrine and autocrine loops related to the activity of epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and their receptors (EGFR, PDGFR) (see Fig. 34.1) [36,37]. Another growth factor related to angiogenesis and vascular re-modeling, vascular endothelial growth factor (VEGF), is also highly expressed in meningiomas [20-22, 38]. The expression levels of VEGF appear to be related to the degree of edema associated with the tumor and, to a lesser extent, to tumor grade. However, VEGF expression levels do not correlate well with the vascular density of meningiomas.

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