Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas

Abstract

The NF2 gene is a putative tumor-suppressor gene that, when it is altered in the germline, causes neurofibromatosis type 2, a tumor-susceptibility disease that mainly predisposes to schwannomas and meningiomas. The recent isolation of the NF2 gene on chromosome 22 allows the identification of somatic mutations in human tumors. We have searched for mutations of the NF2 gene in 331 primary human tumors using a screening method based on denaturing gradient gel electrophoresis, which allows the detection of mutations in 95% of the coding sequence. Mutations were observed in 17 of 57 meningiomas and in 30 of 89 schwannomas. No mutations were observed for 17 ependymomas, 70 gliomas, 23 primary melanomas, 24 pheochromocytomas, 15 neuroblastomas, 6 medulloblastomas, 15 colon cancers, and 15 breast cancers. All meningiomas and one-half of the schwannomas with identified NF2 mutations demonstrated chromosome 22 allelic losses. We conclude that the involvement of the NF2 gene in human tumorigenesis may be restricted to schwannomas and meningiomas, where it is frequently inactivated by a two-hit process.

Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation

“…The proposed domains in merlin that mediate these interactions are depicted. Protein 4.1 growth suppression meningiomas and schwannomas; merlin expression is lost in 60% of sporadic meningiomas and 80% of sporadic schwannomas (Bianchi et al, 1994;Ruttledge et al, 1994;Twist et al, 1994;Merel et al, 1995;Gutmann et al, 1997). In addition, re-expression of wild-type merlin in NF2-deficient schwannoma and meningioma cell lines in vitro results in growth suppression (Sherman et al, 1997;Ikeda et al, 1999), and mice with a targeted mutation in the Nf2 gene (Nf2 +/-mice) are prone to the development of malignant and metastatic tumors .…”

NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas

“…These neoplasms are usually sporadic, but a few families have been described with multiple tumors inherited in an autosomal dominant fashion (Memon, 1980;Battersby et al, 1986;Butti et al, 1989;Domenicucci et al, 1989), and they also occur in as many as half of the patients with the dominantly inherited familial neuro®bromatosis type 2 syndrome (NF2) (Martuza and Eldridge, 1988). Using positional cloning approaches, the candidate gene for NF2 has been isolated from chromosome 22q12 region (Rouleau et al, 1993;Trofatter et al, 1993), and mutations have been observed in both germ-line of NF2 patients and in about 30% of sporadic meningiomas Lekanne-Deprez et al, 1994;Merel et al, 1995;Papi et al, 1995;De Vitis et al, 1996;Harada et al, 1996). These ®ndings indicate that inactivation of the NF2 gene is important in the development of a signi®cant number of sporadic cases that also generally display LOH for markers located on chromosome 22.…”

The Neurofibromatosis Type 2 Gene Product, merlin, Reverses the F-Actin Cytoskeletal Defects in Primary Human Schwannoma Cells

“…The NF2 gene on human chromosome 22q12 was cloned (36,47), enabling mutational analysis of patient blood samples and "second-hit" analysis of NF2-related tumors. Most NF2 patient tumors and sporadic schwannomas have biallelic inactivating mutations in the NF2 gene (3,8,25,31,37), consistent with its action as a tumor suppressor. Schwannomatosis patients do not carry NF2 germ line mutations, and the molecular basis of their disease remains unknown, yet schwannomas from schwannomatosis patients also have biallelic NF2 mutations (19).…”