Screening for mutations in the neurofibromatosis type 2 (NF2) gene in sporadic meningiomas

Abstract

Meningiomas are benign tumors of the central nervous system. They are usually sporadic but can also occur associated with the neurofibromatosis type 2 (NF2) syndrome. The gene responsible for NF2, recently isolated from chromosome 22, encodes a membrane-organizing protein that shows high sequence homology to a protein family thought to link the cytoskeleton with membrane proteins. Mutations of the NF2gene have been described in sporadic meningiomas, exclusively in tumors that show loss of heterozygosity (LOH) of 22q. These preliminary results indicate that the NF2 gene is involved in the pathogenesis of at least a subset of meningiomas, where it does indeed behave as a tumor suppressor gene. In order to characterize better the role of the NF2 gene in the genesis of meningiomas we have examined the entire coding sequence of the gene in 125 meningiomas by single-strand conformational polymorphism analysis; furthermore, LOH analysis for markers of 22q has been carried out. Inactivating mutations were identified in 30% of our samples, all of which also showed LOH of 22q. The majority of mutations identified were frameshifts and nonsense mutations, which are predicted to produce a truncated or nonfunctional protein. We also found two missense and three in-frame deletions that may pinpoint specific regions of the protein critical to its function. Furthermore, the distribution of mutations throughout the gene, suggested that exons 2, 3, 5, 11 and 13 are more frequently involved. Our results reconfirm the importance of the NF2 gene in the pathogenesis of meningiomas and also suggest that there may be a nonrandom clustering of mutations throughout the gene.

Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system

“…Almost all cases with mutations in NF2 have been shown to carry NF2 loss simultaneously. 10,11,[25][26][27][28] Therefore, the result of I-FISH in these cases could be a false negative, suggesting the higher sensitivity and specificity of the amplicon-sequencing system for copy-number alterations. By contrast, one case showed monosomy 22 by I-FISH but did not show NF2 loss by next-generation sequencing, indicating the value of I-FISH as a laboratory examination for copy-number alterations.…”

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

“…There is a clear association between genotype and phenotype in NF2 patients, with nonsense/frameshift mutations being associated with earlier onset of symptoms, larger tumour burden and shorter life expectancy [122]. Sporadic VS, which occur in non-NF2 patients, consistently lack expression of detectable Merlin [123], and genetic inactivation of the Nf2 gene also occurs in the majority of sporadic meningiomas [124][125][126], indicating similarities in tumour biology between sporadic and NF2-related VS and meningiomas. Sporadic VS have an incidence of roughly 3,000 per year in the USA, which seems to be rising [127], and sporadic meningiomas are the most common type of brain tumour, accounting for approximately 25% of primary intracranial tumours in the USA [128].…”

Allelic Loss of 14q and 22q, NF2 Mutation, and Genetic Instability Occur Independently of c‐kit Mutation in Gastrointestinal Stromal Tumor

“…The NF2 gene is responsible for neurofibromatosis 2 (NF2), encoding a 595-amino acid protein called schwannomin or merlin (moesin-ezrin-radixin-like protein), that exhibits significant homology to a highly conserved family of proteins that connect the cytoskeleton to components of the plasma membranes. 27,28) The gene is considered to be a tumor suppressor gene and its mutations are detected in multiple tumor types related with NF2 disorder (schwannoma and meningioma) 16,17,28,29) and in NF2-unrelated tumors (mesothelioma and colon cancer). [30][31][32] In the present study, PCR-SSCP analysis demonstrated NF2 gene mutation in two cases, both of which were accompanied by 22q-LOH: 8 bp was deleted on the splice donor site of the exon 7 in one case, and a 1-bp insertion on exon 4 resulted in a premature stop codon in the other.…”