Molecular Genetics of Neurofibromatosis 2 and Related Tumors (Acoustic Neuroma and Meningioma)<sup>a</sup>

Fontaine, Bertrand; Rouleau, Guy A.; Seizinger, Bernd R.; Menon, Anil G.; Jewell, Ann; Martuza, Robert L.; Gusella, James F.

doi:10.1111/j.1749-6632.1991.tb37776.x

Cited by 36 publications

(13 citation statements)

References 15 publications

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“…Mutation, allelic inactivation, or loss of the tumor suppressor NF2 gene and its parent chromosome 22 have been implicated in approximately 40%-60% of sporadic meningiomas in addition to those afflicted with neurofibromatosis. 12,22,30,79 NF2 probably plays an early driver role in meningioma formation, given its alteration in both low-grade and highgrade tumors, 70 as well as the development of meningiomas in NF2-knockout mice. 44,45 Multiple hypotheses exist for the mechanism by which alterations in NF2 result in tumor formation.…”

Section: Neurofibromatosis Typementioning

confidence: 99%

Genomic landscape of intracranial meningiomas

Abedalthagafi

Horowitz

et al. 2016

JNS

100

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M eningioMas are the most common primary intracranial neoplasms in adults, accounting for 35.8% of all primary CNS tumors and more than 53% of all benign CNS tumors diagnosed in the US. 65 Autopsy and imaging studies suggest an even higher prevalence, affecting almost 3% of women.98 These lesions are believed to arise from progenitor cells that give rise to both the arachnoid cap cells of the arachnoid layer and fibroblasts that reside in the inner dura mater. 18,45The vast majority of meningiomas are indolent.36 A small percentage, however, display malignant behavior characterized by invasive growth patterns and/or markedly higher recurrence rates. Notably, even meningiomas that lack histological features of malignancy recur at significant rates. Multimodality therapy including surgery and radiation is often used in the management of these subsets of meningioma, but other therapeutic modalities have failed to improve control rates. Aggressive meningiomas and the meningiomatosis that occur in hereditary syndromes remain difficult clinical problems. Although most meningiomas are "benign," there is substantial morbidity associated with recurrence, and clinical management remains challenging for clinicians worldwide.Unbiased genome-and exome-wide sequencing approaches have implicated a central core of gene mutations that are associated with a substantial percentage of these tumors. This information may highlight therapeutic targets and enhance biological classification of meningioma. 12,22 Just as an improved understanding of genomic alterations has changed the way we classify and treat cancers including chronic myelogenous leukemia, melanoma, and lung cancer, similar interrogation of the meningioma genome has revealed potential novel treatment pathways for patients harboring these tumors. Meningiomas are the most common primary intracranial neoplasms in adults. Current histopathological grading schemes do not consistently predict their natural history. Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. Furthermore, the recent application of unbiased nextgeneration sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine.

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Section: Neurofibromatosis Typementioning

confidence: 99%

Genomic landscape of intracranial meningiomas

Abedalthagafi

Horowitz

et al. 2016

JNS

100

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“…Loss of NF2 is found in approximately 50% of sporadic meningiomas [6–9]. With the development of next-generation of sequencing, several recent studies have reported new driver mutations, including TRAF7 , KLF4 , AKT1 , SMO, PIK3CA , NOTCH2 , SMARCB1 , CHEK2 , SMARCE1 and POLR2A , particularly in the remaining half of meningiomas with wild-type NF2 [8, 9, 10, 11].…”

Section: Introductionmentioning

confidence: 99%

Whole-genome sequencing identifies new genetic alterations in meningiomas

et al. 2017

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The major known genetic contributor to meningioma formation was NF2, which is disrupted by mutation or loss in about 50% of tumors. Besides NF2, several recurrent driver mutations were recently uncovered through next-generation sequencing. Here, we performed whole-genome sequencing across 7 tumor-normal pairs to identify somatic genetic alterations in meningioma. As a result, Chromatin regulators, including multiple histone members, histone-modifying enzymes and several epigenetic regulators, are the major category among all of the identified copy number variants and single nucleotide variants. Notably, all samples contained copy number variants in histone members. Recurrent chromosomal rearrangements were detected on chromosome 22q, 6p21-p22 and 1q21, and most of the histone copy number variants occurred in these regions. These results will help to define the genetic landscape of meningioma and facilitate more effective genomics-guided personalized therapy.

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“…The inactivation of the NF2 gene at 22q12 has been identified as one of the most common events associated with meningioma tumorigenesis [5], [6]. It has been reported that the majority of anaplastic meningiomas either show homozygous deletions of CDKN2A , p14 ARF , and CDKN2B , mutations in CDKN2A and p14 ARF , or lack of expression of one or more of these genes [7].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Gene Expression Profiling in Meningioma: Deregulated Signaling Pathways Associated with Meningioma and EGFL6 Overexpression in Benign Meningioma Tissue and Serum

et al. 2012

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Molecular mechanisms underlying the pathogenesis of meningioma are not fully elucidated. In this study, we established differential gene expression profiles between meningiomas and brain arachnoidal tissue by using Affymetrix GeneChip Human U133 Plus 2.0 Array. KEGG pathway analysis demonstrated that PI3K/Akt and TGFβ signaling pathways were up-regulated in fibroblastic meningioma, and focal adhesion and ECM-receptor interaction pathways were activated in anaplastic meningioma. EGFL6 was one of the most up-regulated genes in fibroblastic meningioma by microarray analysis. Quantitative real-time PCR demonstrated that benign meningiomas had significantly higher levels of EGFL6 mRNA than brain arachnoidal tissue and atypical and anaplastic meningiomas (P<0.001). EGFL6 gene was also highly expressed in ovarian cancer, but expressed lowly in other investigated tumors. ELISA analysis showed that patients with benign meningiomas and ovarian cancers had the highest serum levels of EGFL6 (mean concentration: 672 pg/ml for benign meningiomas, and 616 pg/ml for ovarian cancers). Healthy people and patients with other tumors, however, had low levels of serum EGFL6. In conclusion, we proposed that activation of PI3K/Akt and integrin-mediated signaling pathways was involved in the pathogenesis of benign and anaplastic meningiomas, respectively. We also presented evidence that EGFL6 was overexpressed in benign meningioma tissues and serum.

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Molecular Genetics of Neurofibromatosis 2 and Related Tumors (Acoustic Neuroma and Meningioma)^a

Cited by 36 publications

References 15 publications

Genomic landscape of intracranial meningiomas

Genomic landscape of intracranial meningiomas

Whole-genome sequencing identifies new genetic alterations in meningiomas

Analysis of Gene Expression Profiling in Meningioma: Deregulated Signaling Pathways Associated with Meningioma and EGFL6 Overexpression in Benign Meningioma Tissue and Serum

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Molecular Genetics of Neurofibromatosis 2 and Related Tumors (Acoustic Neuroma and Meningioma)a

Cited by 36 publications

References 15 publications

Genomic landscape of intracranial meningiomas

Genomic landscape of intracranial meningiomas

Whole-genome sequencing identifies new genetic alterations in meningiomas

Analysis of Gene Expression Profiling in Meningioma: Deregulated Signaling Pathways Associated with Meningioma and EGFL6 Overexpression in Benign Meningioma Tissue and Serum

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Molecular Genetics of Neurofibromatosis 2 and Related Tumors (Acoustic Neuroma and Meningioma)^a