Analysis of the neurofibromatosis type 2 gene in different human tumors of neuroectodermal origin

Abstract

The autosomal dominant syndrome neurofibromatosis type 2 (NF2) is characterized by the development of bilateral vestibular schwannomas, meningiomas, ependymomas and gliomas. The NF2 gene, recently isolated from chromosome 22, is mutated in both sporadic and NF2 tumors such as schwannomas, meningiomas and ependymomas. Mutations of the gene have been described not only in the neoplasms usually associated with NF2, but also in 30% of the melanomas and 41 % of the mesotheliomas analyzed. In particular, the finding of mutations in melanomas supports the hypothesis that the NF2 gene is involved in the genesis of several tumor types that arise from the embryonic neural crest. In this study we examined, by single-strand conformational polymorphism (SSCP) analysis, 41 tumors of the central nervous system (11 schwannomas and 30 gliomas), 19 melanomas and 15 Merkel cell carcinoma specimens for mutations in the coding sequence of the NF2 gene. We found three inactivating mutations of the NF2 gene in schwannomas. No alterations of the gene were detected by SSCP analysis of the other tumors. These results confirm the role of NF2 in pathogenesis of schwannomas, but do not define its significance in the genesis of the other neuroectodermal tumors studied.

Comprehensive genetic and epigenetic analysis of sporadic meningioma for macro-mutations on 22q and micro-mutations within the NF2 locus

“…Considering what is known to date about the NF2 gene mutational spectrum in different tumors, it can be assumed that at least two of the latter three mutations (M46 – aberrant splicing and M115 – nonsense mutation) are pathogenic. These types of mutations are, however, usually combined with the second inactivating hit on the remaining normal allele of the gene [13,44-47]. The third aberration is a missense mutation (tumor M87, exon 4, 436 G>A, Val-146-Ile, Table 1), which is possibly introducing a dysfunction to the N-terminal FERM domain (residues 1–302 of the protein, plasma membrane binding domain) of the protein.…”

Allele‐specific loss of heterozygosity at the DAL‐1/4.1B (EPB41L3) tumor‐suppressor gene locus in the absence of mutation

“…Although it has been found that NF2 is mutated in most meningiomas and schwannomas (Lekanne Deprez et al, 1994;Merel et al, 1995;Papi et al, 1995;Slavc et al, 1995;De Vitis et al, 1996), some cases lacked expression of the NF2 protein without biallelic NF2 inactivation (Stemmer-Rachamimov et al, 1997). Kimura et al (2000) demonstrated that, in some of these cases, post-translational regulation of merlin through a calpain-mediated proteolysis pathway may be responsible for the absence of NF2 protein.…”

Molecular Biology of Unreresectable Meningiomas: Implications for New Treatments and Review of the Literature

“…46 Modern molecular techniques have demonstrated that the mutation was not only found in meningiomas in patients with NF-2, but also in the majority of patients with sporadic meningiomas. [47][48][49][50][51][52] Most mutations occur in tumors that have already lost one chromosome 22 allele, supporting the ''two-hit'' hypothesis for tumorigenesis ( Fig. 1).…”