Genomic landscape of high-grade meningiomas

Bi, Wenya Linda; Greenwald, Noah F.; Abedalthagafi, Malak; Wala, Jeremiah A.; Gibson, Will J.; Agarwalla, Pankaj K.; Horowitz, Peleg; Schumacher, Steven E.; Esaulova, Ekaterina; Yu, Mei; Chevalier, Aaron; Ducar, Matthew; Thorner, Aaron R.; Hummelen, Paul Van; Stemmer‐Rachamimov, Anat; Artyomov, Maksym; Al‐Mefty, Ossama; Dunn, Gavin P.; Santagata, Sandro; Dunn, Ian F.; Beroukhim, Rameen

doi:10.1038/s41525-017-0014-7

Cited by 150 publications

(180 citation statements)

References 64 publications

(115 reference statements)

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“…A major difference between our study and previous explorations of the genomic landscape of meningioma is that those studies maintained the framework of the existing WHO histopathological classification for their molecular analysis (13,(15)(16)(17)(18)(19)44). For example, one study of atypical (grade II) tumors found the majority to have NF2/chr22q loss and genomic instability along with overexpression of the E2F2 and FOXM1 transcriptional networks (13).…”

Section: Discussionmentioning

confidence: 83%

“…Since high-grade meningiomas have more chromosomal abnormalities (13,18), we analyzed the three types of tumors for genomic instability using copy number data derived from whole-exome sequencing (WES) ( Fig. 4).…”

Section: Copy Number and Somatic Alterations In Meningiomasmentioning

confidence: 99%

“…Harmanci et al found that a majority of primary atypical meningiomas have loss of NF2 along with either genomic instability or SMARCB1 mutations (13); this combination of features was not able to completely separate atypical from benign tumors, but the addition of the top 25 most differentially expressed genes raised the prediction accuracy of the model to 91% for atypical tumors with a high or medium Ki-67 index. Bi et al found that grade III tumors are less likely to have TRAF7, KL4, AKT1, or SMO mutations but more likely to show genomic instability (copy number variation or CNV) (18). Vasudevan et al sought targetable pathways in high-grade meningiomas and found that high FOXM1 expression is associated with poor clinical outcomes (19); this is one of several studies showing that DNA methylation profiles have clinical relevance (14,(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

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Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Patel

Wan

Al‐Ouran

et al. 2019

Preprint

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Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors. Significance StatementMeningiomas are the most common primary brain tumors. Although most of these tumors are benign, one-fifth will recur despite apparently complete resection. Several studies have demonstrated that genomic approaches can yield important insights into the biology of these tumors. We performed RNA sequencing and whole-exome sequencing of 160 tumors from 140 patients, which identified three distinct groups of meningioma that correlate with recurrence better than the current WHO grading system. Our analysis also revealed that the most aggressive type was characterized by loss of the repressive DREAM complex. These findings should improve prognostication for patients and lead to viable therapeutic targets.

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Section: Discussionmentioning

confidence: 83%

Section: Copy Number and Somatic Alterations In Meningiomasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Patel

Wan

Al‐Ouran

et al. 2019

Preprint

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“…Mutations in LRP1B, a gene previously described as mutated in high-grade meningiomas [20], were detected in nine chordoid meningiomas, and occurred in tumors from both ED group #2 (25%) and ED group #3 (41%), without apparent predilection for location ( Figure 2A,C). LRP1B encodes a large low-density lipoprotein (LDL) receptor family member with tumor suppressor activity [21].…”

Section: Chordoid Meningioma Ed Groups Exhibit Distinct Gene Mutationmentioning

confidence: 90%

Mutation Status and Epithelial Differentiation Stratify Recurrence Risk in Chordoid Meningioma—A Multicenter Study with High Prognostic Relevance

Georgescu

Nanda

et al. 2020

Cancers

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Chordoid meningioma is a rare WHO grade II histologic variant. Its molecular alterations or their impact on patient risk stratification have not been fully explored. We performed a multicenter, clinical, histological, and genomic analysis of chordoid meningiomas from 30 patients (34 tumors), representing the largest integrated study to date. By NHERF1 microlumen immunohistochemical detection, three epithelial differentiation (ED) groups emerged: #1/fibroblastic-like, #2/epithelial-poorly-differentiated and #3/epithelial-well-differentiated. These ED groups correlated with tumor location and genetic profiling, with NF2 and chromatin remodeling gene mutations clustering in ED group #2, and TRAF7 mutations segregating in ED group #3. Mutations in LRP1B were found in the largest number of cases (36%) across ED groups #2 and #3. Pathogenic ATM and VHL germline mutations occurred in ED group #3 patients, conferring an aggressive or benign course, respectively. The recurrence rate significantly correlated with mutations in NF2, as single gene, and with mutations in chromatin remodeling and DNA damage response genes, as groups. The recurrence rate was very high in ED group #2, moderate in ED group #3, and absent in ED group #1. This study proposes guidelines for tumor recurrence risk stratification and practical considerations for patient management.

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“…Many meningiomas possess a normal karyotype, with an overall low incidence of genomic alterations (i.e., somatic copy number alterations (SCNA), rearrangements, mutational burden) (10)(11)(12)(13). However, these disruptions increase in accordance with tumor grade and aggressiveness.…”

Section: Cyotgeneticsmentioning

confidence: 99%

Recent Advances in Meningioma Immunogenetics

2020

Self Cite

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Meningiomas are relatively common, and typically benign intracranial tumors, which in many cases can be cured by surgical resection. However, less prevalent, high grade meningiomas, grow quickly, and recur frequently despite treatment, leading to poor patient outcomes. Across tumor grades, subjective guidelines for histological analysis can preclude accurate diagnosis, and an insufficient understanding of recurrence risk can cloud the choice of optimal treatment. Improved diagnostic and prognostic markers capable of discerning between the 15 heterogeneous WHO recognized meningioma subtypes are necessary to improve disease management and identify new targeted drug treatments. In this review, we show the advances in molecular profiling and immunophenotyping of meningiomas, which may lead to the development of new personalized therapeutic strategies.

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Genomic landscape of high-grade meningiomas

Cited by 150 publications

References 64 publications

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Mutation Status and Epithelial Differentiation Stratify Recurrence Risk in Chordoid Meningioma—A Multicenter Study with High Prognostic Relevance

Recent Advances in Meningioma Immunogenetics

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