Chromosome 22q:NF2Gene and the Gene Protein Product, Schwannomin/merlin

The link between chromosome 22 abnormalities and meningiomas was first suspected in patients with NF2. The hallmark of this disease is bilateral acoustic schwannomas. Interestingly, meningiomas occur in ~50% of patients with NF2. The NF2 tumor suppressor gene, located on chromosome 22q12.1, and its protein product, schwannomin or merlin ( Figs. 6.3 and 6.4 ), have been identified in cytogenetic and molecular studies.1,2 The NF2 gene codes for the schwannomin/merlin tumor suppressor (TuS) protein (moesin-, ezrin-, radixin-like protein), which is a part of the band 4.1 families of cyto-skeleton-associated proteins ( Fig. 6.4 ; Table 6.1 ).1,2 Possible functions of schwannomin/merlin include roles in cytoskeletal functions (e.g., contact inhibition) and secondary signaling pathways (e.g., Ras) ( Fig. 6.4 ).2,4 Insertions or deletions of this gene produce a nonfunctional merlin protein, resulting in decreased cell adhesion and tumorigenesis.4 Reduced schwannomin/merlin expression has been demonstrated in sporadic meningiomas.5

Interestingly, the frequency of NF2 gene mutation varies between meningioma subtypes. Among the three most common meningioma World Health Organization (WHO) grade I subtypes, 70 to 80% of fibroblastic and transitional meningiomas show NF2 gene mutations, whereas the meningothelial subtype shows NF2 mutations only 25% of the time, suggesting that cytogenetic differences in the tumorigenesis of meningioma subtypes may exist.6 In both atypical and anaplastic meningiomas, the frequency of NF2 gene mutations is ~70%.3 Therefore, NF2 gene mutations are probably involved with tumori-genesis but not tumor progression. In vivo mice experiments have provided further support for this theory but suggest that merlin loss alone is not sufficient for meningioma development.7

A search for a second tumor suppressor gene on 22q stems from the discrepancy between the frequency of chromosome 22 LOH, which exceeds that of NF2 gene abnormalities.6 Deletions of chromosome 22 are found in all NF2-associated meningiomas and in 54 to 78% of sporadic meningiomas. Further analysis of the NF2 gene in sporadic meningiomas reveals that roughly one third to one half of these tumors have an inactivating mutation, often accompanied by loss of the other allele. These studies have resulted in other possible gene candidates ( Fig. 6.3 ; Table 6.1 ).2

Chromosome 1

Deletions of the short arm of chromosome 1 are the second most frequent alteration detected by cytogenetic analysis of meningiomas ( Table 6.1 ).2,3 FISH studies showing monosomy 1p in 70% of atypical and almost 100% of anaplastic meningiomas indicate a correlation between loss of chromosome 1p and meningioma progression. Loss of 1p also correlates with tumor recurrence; the rate of recurrence is 30% with loss of 1p but only 4.3% when 1p is retained.8 Which gene on the 1p arm results in the clinical effects on tumor is unknown, but research has suggested alkaline phosphatase as a possible tumor suppressor whose location on chromosome 1p (1p34→1p36.1) and loss of function are correlated with higher-grade meningiomas ( Table 6.1 ).3,8

Other Meningioma Chromosomal Abnormalities

Many cytogenetic abnormalities are associated with meningioma progression and typical or anaplastic histology. These chromosomal aberrations include the presence of dicentric or ring chromosomes, losses of chromosome arms 1p, 6q, 7, 9p, 10, 14q, 18q, 19, or 20, and gains/amplifications of 1q, 9q, 12q, 15q, 17q, or 20q ( Fig. 6.2 ).3,8,9 It is unknown how these chromosome changes lead to tumor progression, although several chromosomes and genes appear to have specific associations with benign, atypical, and anaplastic meningioma grades. For example, benign meningiomas are more liable to have 14q deletions.3 Roughly two thirds of anaplastic meningiomas exhibit altered cell-cycle checkpoint tumor suppressor genes located on chromosome 9p ( Table 6.1 ). Further evidence implicating these deletions in meningioma pathogenesis comes from the significantly shorter survival times of patients. Other rare molecular abnormalities include phosphatase and tensin homologue gene deletion, cyclin-dependent kinase inhibitor 2c gene deletion, and ribosomal protein S6 kinase gene amplification.1,2

Cytogenetic alterations can also include changes in chromosome number. Sixty percent of meningiomas have been found to be hypodiploid, 33% diploid, 4.5% hyperdiploid, and 2.5% hypotriploid.10 Complex karyo-types with hypodiploidy, structural rearrangements such as ring chromosomes, dicentrics, double minutes, and association between satellites seem to be associated with aggressive tumor characteristics.3 Identification of a microsatellite instability phenotype in meningiomas has also been described. Finally, studies have identified what appear to be sporadic, familial, radiation-induced, and pediatric meningiomas.2,11 Mounting evidence suggests that these tumors are genetically different, which may explain the more aggressive nature of the familial, radiation-induced, and pediatric cases.2,11