Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1).

Children with neurofibromatosis 1 (NF1) often develop low-grade gliomas, but brain tumors are infrequently encountered in adults with NF1. The authors present evidence from two clinical series, one including patients known to have NF1 and another focusing on adults with new onset brain tumors, that suggests an association between NF1 and symptomatic gliomas in older individuals. They also summarize the clinical data on 17 adolescents or adults with NF1 and symptomatic gliomas. The findings suggest that individuals with NF1 are at increased risk of developing gliomas throughout their lives.

Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities.

Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, other benign neural tumors, and cataracts. Patients in some families develop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutations result in a truncated protein and severe NF2. To look for additional mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsense mutations, 2 frameshifts, 7 splice-site mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnosis, numbers of meningiomas, spinal and skin tumors, and presence of cataracts and retinal abnormalities. We compared clinical findings in patients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P < or = .05) for nearly every variable. Patients with nonsense or frameshift mutations were younger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and frameshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences between the two groups were observed only for mean ages at onset and at diagnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patients from five families with four different nonsense mutations. This finding, which may represent a new genotype-phenotype correlation, merits further study.

Exon scanning for mutations of the NF2 gene in pediatric ependymomas, rhabdoid tumors and meningiomas.

Deletions of chromosome 22 have been identified in 3 types of childhood primary brain tumor: meningiomas, rhabdoid or atypical teratoid tumors (ATT) and ependymomas. This implicates the involvement of tumor suppressor genes on chromosome 22 in the genesis of these rare tumors. One such candidate tumor suppressor gene is the recently cloned neurofibromatosis 2 (NF2) locus. The purpose of our study was to determine the frequency of germ-line and somatic NF2 mutations in a selected group of brain tumors in children. Using single-strand conformation polymorphism (SSCP) assays we screened 17 exons of the NF2 gene in 13 pediatric brain tumors and 9 matched normal blood DNA samples. Tumors included 3 meningiomas, 2 rhabdoid or ATTs, 7 ependymomas and 1 malignant tumor of glial lineage. In addition, lymphoblastoid cell lines from 3 patients with rhabdoid/ATT in whom no tumor tissue was available were analyzed for germ-line mutations. Migration shifts were not detected in any of the normal DNA samples analyzed. Of the 13 tumors screened by SSCP, 1 meningioma with monosomy 22 produced a migration shift in exon 13. DNA sequencing of exon 13 revealed a deletion of a single guanine nucleotide (base 1397) in codon 466, causing a frame shift. While not all mutations might have been picked up by this technique, the data suggest that, similar to adult sporadic meningiomas, some pediatric meningiomas may result from somatic mutations in the NF2 gene. For rhabdoid tumors and ependymomas it appears that a locus distinct from NF2 might be responsible for tumorigenesis.

Analysis of the neurofibromatosis 2 gene in human ependymomas and astrocytomas.

Ependymomas and astrocytomas commonly have allelic losses of chromosome 22q, which suggests the presence of a glioma tumor suppressor gene on 22q. A candidate tumor suppressor gene on 22q is the neurofibromatosis 2 (NF2) gene since NF2 patients have an increased susceptibility to ependymomas and astrocytomas. Using single strand conformation polymorphism analysis and direct DNA sequencing, we screened 8 ependymomas and 30 fibrillary astrocytomas from non-NF2 patients for mutations in the coding sequence and portions of the 3' untranslated region of the NF2 gene. Only one mutation was detected, a single base deletion in NF2 exon 7 from a spinal ependymoma, which had also lost the wild-type allele. These results suggest that the NF2 gene may be important in the formation of some ependymomas but the NF2 gene is probably not the critical chromosome 22q tumor suppressor gene involved in astrocytoma tumorigenesis.

A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder characterized by the occurrence of bilateral vestibular schwannomas and other central nervous system tumors including multiple meningiomas. Genetic linkage studies and investigations of both sporadic and familial tumors suggest that NF2 is caused by inactivation of a tumor suppressor gene in chromosome 22q12. We have identified a candidate gene for the NF2 tumor suppressor that has suffered nonoverlapping deletions in DNA from two independent NF2 families and alterations in meningiomas from two unrelated NF2 patients. The candidate gene encodes a 587 amino acid protein with striking similarity to several members of a family of proteins proposed to link cytoskeletal components with proteins in the cell membrane. The NF2 gene may therefore constitute a novel class of tumor suppressor gene.