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Multiple meningiomas: differential involvement of the NF2 gene in children and adults.

ABSTRACT: OBJECTIVE: To screen for NF2 mutations in people with meningiomas. METHODS: Lymphocyte or tumour DNA was analysed from 46 individuals from 36 families who presented with a meningioma at age < or =15 years without vestibular schwannoma (VS), or who had multiple meningiomas in adulthood before the diagnosis of VS. RESULTS: Eight of 13 people with meningioma and other features of neurofibromatosis 2 (NF2) had an identified constitutional NF2 mutation in blood DNA, but none of the other subjects had identified constitutional NF2 mutations. CONCLUSIONS: Constitutional NF2 mutations are the most likely cause of meningioma in children and in people with a meningioma plus other non-VS features of NF2. Mosaic NF2 may be the cause of about 8% of multiple meningiomas in sporadic adult cases, but there are other causes in the majority of other such patients and in multiple meningioma in families.

SUBMITTER: Evans DG

PROVIDER: S-EPMC1735900 | biostudies-other | 2005 Jan

REPOSITORIES: biostudies-other

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Multiple meningiomas: differential involvement of the NF2 gene in children and adults.

Evans D G R DG Watson C C King A A Wallace A J AJ Baser M E ME

Journal of medical genetics 20050101 1

<h4>Objective</h4>To screen for NF2 mutations in people with meningiomas.<h4>Methods</h4>Lymphocyte or tumour DNA was analysed from 46 individuals from 36 families who presented with a meningioma at age < or =15 years without vestibular schwannoma (VS), or who had multiple meningiomas in adulthood before the diagnosis of VS.<h4>Results</h4>Eight of 13 people with meningioma and other features of neurofibromatosis 2 (NF2) had an identified constitutional NF2 mutation in blood DNA, but none of the ...[more]

PMID: 15635074

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Project description:BACKGROUND:Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date. METHODS:850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed. RESULTS:Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n?=?426, 50%), was associated with male sex (64.4% %, p?=?0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERT promoter (TERTp; n?=?56) or TP53 mutations (n?=?25) and were either NF2-mutant or wild-type, and displayed no association with either sex (p?=?0.39). The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases-with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n?=?22) or PBRM1 (n?=?16). A second subgroup contained AKT1 (n?=?26), PIK3CA (n?=?14) and SMO (n?=?7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations. CONCLUSIONS:Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease. Overall, these data increase our understanding of the pathobiology of high-grade/progressive meningiomas and can guide the design of clinical trials. IRB APPROVAL STATUS:Reviewed and approved by Western IRB; Protocol No. 20152817.

Dataset Information

Multiple meningiomas: differential involvement of the NF2 gene in children and adults.

Publications

Multiple meningiomas: differential involvement of the NF2 gene in children and adults.

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