The Role of Merlin/NF2 Loss in Meningioma Biology

Lee, Sungho; Karas, Patrick J.; Hadley, Caroline; Bayley, James C.; Khan, A. Basit; Jalali, Ali; Sweeney, Alex D.; Klisch, Tiemo J.; Patel, Akash J.

doi:10.3390/cancers11111633

Cited by 63 publications

(63 citation statements)

References 85 publications

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“…Unsupervised clustering of the tumors based on their whole-transcriptome profiles revealed three distinct groups that did not directly correlate the WHO grades, but reliably predicted aggressive clinical behavior such as frequency of tumor recurrence. The authors proposed a novel classification that links molecular profile of meningiomas with their potential to recur: (1) benign tumors that carry intact NF2, but have mutations in other genes (e.g., TRAF7, AKT1, KLF4); (2) benign tumors that carry biallelic loss of NF2 and presented with SWI/SNF and PRC2 gene involvement; and (3) aggressive meningiomas with high risk of recurrence that have inactivated NF2 and carry chromosome 1p loss and the loss of the repressor function of DREAM, a chromatin-remodeling complex involved in cell cycle progression 38 . These findings underscore the importance of molecular profiling of meningiomas and the limitations of the WHO grading system.…”

Section: Discussionmentioning

confidence: 99%

Comparative clinical and genomic analysis of neurofibromatosis type 2-associated cranial and spinal meningiomas

Pemov

Dewan

Hansen

et al. 2020

Sci Rep

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Neurofibromatosis type 2 (NF2) is an autosomal dominant Mendelian tumor predisposition disorder caused by germline pathogenic variants in the tumor suppressor NF2. Meningiomas are the second most common neoplasm in NF2, often occurring in multiple intracranial and spinal locations within the same patient. In this prospective longitudinal study, we assessed volumes and growth rates of ten spinal and ten cranial benign meningiomas in seven NF2 patients that concluded with surgical resection and performed whole-exome sequencing and copy-number variant (CNV) analysis of the tumors. Our comparison of the volume and the growth rate of NF2-associated spinal and cranial meningiomas point to the differences in timing of tumor initiation and/or to the differences in tumor progression (e.g., non-linear, saltatory growth) at these two anatomical locations. Genomic investigation of these tumors revealed that somatic inactivation of NF2 is the principal and perhaps the only driver of tumor initiation; and that tumor progression likely occurs via accumulation of CNVs, rather than point mutations. Results of this study contribute to a better understanding of NF2associated meningiomas clinical behavior and their genetic underpinnings. Neurofibromatosis type 2 (NF2) is a rare hereditary neoplasia syndrome, with an estimated incidence of 1:25,000-1:33,000 1,2. Although the hallmark and primary definitive diagnostic criterion of NF2 is the presence of bilateral vestibular schwannomas, meningiomas are the next most frequently identified tumor in these patients 3,4. It is estimated that 45-58% of NF2 patients harbor intracranial meningiomas and 20% have spinal meningiomas 5-7. Meningiomas in NF2 are typically WHO grade 1, slow-growing, benign tumors. When present, meningiomas in NF2 patients are often multiple, which contributes significantly to morbidity and mortality. Although symptoms are primarily due to the direct mass effect of tumor upon adjacent brain and cranial nerves, tumors may also evoke seizures and obstruct venous outflow causing cerebral edema 6. A case series examining 287 cranial meningiomas from NF2 patients confirmed that similar to their sporadic counterparts, the majority of NF2-associated meningiomas (95.8%) were grade 1 by WHO guidelines. Although only 4.2% of total meningiomas were grade 2 or 3, 35% of growing or symptomatic resected meningiomas were grade 2/3. Growth rate was generally slow, although 7.3% of meningiomas examined by MRI analysis displayed an annual volumetric growth rate of 20% or higher 8. The cumulative burden of intracranial meningiomas in NF2 patients results in a 2.51-fold greater risk of mortality when compared to NF2 patients without intracranial meningiomas 9 .

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Section: Discussionmentioning

confidence: 99%

Comparative clinical and genomic analysis of neurofibromatosis type 2-associated cranial and spinal meningiomas

Pemov

Dewan

Hansen

et al. 2020

Sci Rep

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“…Additionally, Merlin protein expression was not analyzed in this study; however, it is plausible that the meningioma cells exhibited somatic mutations in NF2, and therefore had non-functional Merlin. The loss of Merlin results in increased tumor cell proliferation due to loss of contact inhibition mechanisms [9][10][11]. Although NF2 mutations are the most common, somatic mutations on other genes such as BAM22 and BCR on chromosome 22 have also been shown to play a role in meningioma tumorigenesis [12].…”

Section: Discussionmentioning

confidence: 99%

Gross and Histological Examination of a Large Spheno-Orbital Meningioma

Kaiser¹,

Reddy²,

Zimmerman³

et al. 2020

Cureus

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Meningiomas arise from arachnoid cap cells and are the most common heavily researched intracranial tumors. Most of these neoplasms are benign and are classified as World Health Organization (WHO) grade I. They are often found in parasagittal and falx regions, over cerebral convexities, and in the sphenoid ridges. Spheno-orbital meningiomas (SOMs) occupy the cranium and the orbit and are less commonly encountered. Nonetheless, in this case study, a 9.5 cm × 5 cm SOM occurring in a 93-year-old female cadaver was identified and examined. The tumor spanned from the left middle cranial fossa, through the anterior fossa and invaded the orbit. It caused proptosis of the left eye, compression of the temporal lobe, and damage to the optic nerve. Histological examination of the tumor revealed characteristics of a WHO grade I meningothelial meningioma.

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“…Allelic losses (loss of heterozygosity (LOH)) of this region are found in 40-70% of sporadic and the vast majority of NF2 associated meningiomas. Additionally, NF2 mutations are found in up to 60% of tumors, consistent with a classic two-hit mechanism of tumor suppressor gene inactivation [2,[14][15][16][17]. Usually, it is proposed that meningiomas progress from low-grade to high-grade tumors, although this is not always easy to be demonstrated [18], and cytogenetic studies propose a higher amount of chromosomal gains and losses according to the grade of tumors [19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 98%

Meningiomas: An Overview of the Landscape of Copy Number Alterations in Samples from an Admixed Population

Silveira

Ferreira

Amorim

et al. 2020

Journal of Oncology

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Meningiomas are considered the most common intracranial tumors, affecting mainly women. Studies in mixed populations can be of great importance to clarify issues related to the genetic diversity of tumors and their development. Considering that data obtained from analyses of the profile of copy number alterations (CNA) have been a useful diagnostic indicator for many types of tumors and that meningiomas show a complex pattern of gains and losses in the number of copies, our objective was to analyze the CNA profile in 33 samples of meningiomas of different histological grades (WHO Grade I-III) from patients in a city located in the Amazon region of Brazil, using aCGH. We found that the female to male ratio was 3 : 1. The aCGH analysis revealed a total of 2304 CNA, with an average of 69.8 ± 57.4 per case, of which 1197 were gains (52%), 926 were losses (40.2%), 105 were amplifications (4. 5%), and 76 were deletions (3.3%). A significant relationship was observed between the type of CNA and the degree of the tumor (chi-square test: χ2 = 65,844; p<0.0001; contingency coefficient: C = 0.1772; p<0.0001). Evaluating the recurrent changes in at least 50% of the samples, we observe as the most frequent losses of the segments 22q13.1-q13.2 (82%), 1p35.3 (76%), and 14q13.1-q13.2 (67%), involving all histopathological grades. The analysis of these regions showed the inclusion of genes with functions such as regulation, maintenance of cell survival, reorganization of the cytoskeleton, cell signaling, and DNA repair, among others. However, overall, the profiles observed in meningiomas of this admixed population were very similar to the ones observed in Caucasian groups. An interesting finding was a recurrent gain of 8p22 observed only in grade I meningiomas, a region which includes DLC1, a suppressor candidate gene probably implicated in the developments or progression of meningiomas, usually found deleted, when related to CNAs.

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The Role of Merlin/NF2 Loss in Meningioma Biology

Cited by 63 publications

References 85 publications

Comparative clinical and genomic analysis of neurofibromatosis type 2-associated cranial and spinal meningiomas

Comparative clinical and genomic analysis of neurofibromatosis type 2-associated cranial and spinal meningiomas

Gross and Histological Examination of a Large Spheno-Orbital Meningioma

Meningiomas: An Overview of the Landscape of Copy Number Alterations in Samples from an Admixed Population

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