Genomic Profiling Reveals Alternative Genetic Pathways of Meningioma Malignant Progression Dependent on the Underlying<i>NF2</i>Status

Goutagny, Stéphane; Yang, Hong; Zucman‐Rossi, Jessica; Chan, Jennifer A.; Dreyfuss, Jonathan M.; Park, Peter J.; Black, Peter McLaren; Giovannini, Marco; Carroll, Rona S.; Kalamaridès, Michel

doi:10.1158/1078-0432.ccr-10-0891

Cited by 105 publications

(87 citation statements)

References 40 publications

(37 reference statements)

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“…34,38,39,62,78 In addition to dysregulation of specific signaling pathways, NF2-mutated meningiomas may also exhibit greater chromosomal instability than NF2-wild type counterparts. 32 However, no targetable dependency in the NF2 pathway currently exists.…”

Section: Neurofibromatosis Typementioning

confidence: 99%

Genomic landscape of intracranial meningiomas

Abedalthagafi

Horowitz

et al. 2016

JNS

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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

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“…7-12 A recent genomic study demonstrated that there were two main pathways of progression in meningiomas: one linked to bi-allelic NF2 loss and genomic instability, and the other characterized by the absence of chromosome imbalances. 13 As the mechanism underlying NF2-related genomic instability is…”

Section: Introductionmentioning

confidence: 99%

Meningioma progression in mice triggered by Nf2 and Cdkn2ab inactivation

et al. 2012

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Aggressive variants of meningiomas (WHO grade II and III) represent up to 30% of those tumors that are among the most common primary central nervous system tumors in adults. Currently, there is no effective treatment for grade-II and -III meningiomas, the main treatment remaining surgical excision. Genetic studies have highlighted two main events associated with meningioma progression: an increase of chromosomal instability in tumors with NF2 inactivation and homozygous deletions or point mutations of the CDKN2AB locus. In this study we demonstrated that in mice, in addition to bi-allelic Nf2 inactivation, homozygous and heterozygous Adenovirus Cre-mediated Cdkn2ab deletions lead to increased meningioma frequency (72% and 50%, respectively) with a shorter latency (3.5 and 7.8 months, respectively) compared with control cohorts and induce grade II/III meningioma progression with an incidence of 34% and 28%, respectively. Moreover, Cdkn2ab inactivation in arachnoidal cells was associated with decreased senescence compared with Nf2(-/-) and wild-type arachnoidal cells in vitro. We have established three mouse meningioma cell lines and generated a syngenic orthotopic meningioma mouse model with 50-100% grade-II/III meningiomas after reimplantation. Comparative genomic hybridization of four meningiomas from Cdkn2ab homozygous mice and three cell cultures revealed the absence of unbalanced chromosomal segments in tumors and several chromosome imbalances in cell cultures. In addition, we were able to detect meningiomas by using bioluminescence and to evaluate tumor vascular permeability by dynamic magnetic resonance imaging. These results show that Nf2 and Cdkn2ab cooperate to promote meningioma progression in mice. The short latency of tumor development and the ability to derive grade II/III meningioma cell cultures are key aspects of this model to promote its use in pre-clinical drug testing.

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“…While SNP arrays have been used in the characterization of many types of tumors, to the best of our knowledge, few studies have been reported so far in which they have been applied to analyze large series of meningiomas. In fact, until now only 100K SNP arrays have been used to characterize an atypical meningioma (Krupp et al, 2008) and 18 meningiomas have been studied with 500K arrays (Goutagny et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Delineation of commonly deleted chromosomal regions in meningiomas by high‐density single nucleotide polymorphism genotyping arrays

Tabernero

Maíllo

Nieto

et al. 2012

Genes Chromosomes & Cancer

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Despite recent advances in the identification of the cytogenetic profiles of meningiomas, a significant group of tumors still show normal karyotypes or few chromosomal changes. The authors analyzed the cytogenetic profile of 50 meningiomas using fluorescence in situ hybridization and high‐density (500 K) single nucleotide polymorphism (SNP) arrays. Our results confirm that del(22q) (52%) and del(1p) (16%) (common deleted regions: 22q11.21‐22q13.3. and 1p31.2‐p36.33) are the most frequent alterations. Additionally, recurrent monosomy 14 (8%), del(6q) (10%), del(7p) (10%), and del(19q) (4%) were observed, while copy number patterns consistent with recurrent chromosomal gains, gene amplification, and copy number neutral loss of heterozygosity (cnLOH) were either absent or rare. Based on their overall SNP profiles, meningiomas could be classified into: (i) diploid cases, (ii) meningiomas with a single chromosomal change [e.g., monosomy 22/del(22q)] and (iii) tumors with ≥2 altered chromosomes. In summary, our results confirm and extend on previous observations showing that the most recurrent chromosomal abnormalities in meningiomas correspond to chromosome losses localized in chromosomes 1, 22 and less frequently in chromosomes 6, 7, 14, and 19, while chromosomal gains and cnLOH are restricted to a small proportion of cases. Finally, a set of cancer‐associated candidate genes associated with the TP53, MYC, CASP3, HDAC1, and TERT signaling pathways was identified, in cases with coexisting monosomy 14 and del(1p). © 2012 Wiley Periodicals, Inc.

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Genomic Profiling Reveals Alternative Genetic Pathways of Meningioma Malignant Progression Dependent on the UnderlyingNF2Status

Cited by 105 publications

References 40 publications

Genomic landscape of intracranial meningiomas

Genomic landscape of intracranial meningiomas

Meningioma progression in mice triggered by Nf2 and Cdkn2ab inactivation

Delineation of commonly deleted chromosomal regions in meningiomas by high‐density single nucleotide polymorphism genotyping arrays

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