Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma

Magill, Stephen T.; Vasudevan, Harish N.; Seo, Kyounghee; Villanueva-Meyer, Javier; Choudhury, A.; Liu, S. John; Pekmezci, Melike; Findakly, Sarah; Hilz, Stephanie; Lastella, Sydney; Demaree, Benjamin; Braunstein, Steve; Bush, Nancy Ann Oberheim; Aghi, Manish K.; Theodosopoulos, Philip V.; Sneed, Penny K.; Abate, Adam R.; Berger, Mitchel S.; McDermott, Michael W.; Lim, Daniel; Ullian, Erik M.; Costello, J; Raleigh, David R.

doi:10.1038/s41467-020-18582-7

Cited by 59 publications

(45 citation statements)

References 84 publications

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“…By manual macrodissection or LMD, we studied the phenotypic and genotypic intratumour heterogeneity in 25 spatially distinct tumour areas from 13 malignant meningiomas. Our data reveal regional alterations and tumour heterogeneity in two cases (one atypical and the other anaplastic), in agreement with previous studies in the literature [35,36], that the biological behaviour could explain. Recently, a spatial heterogeneity at molecular and radiographic level has been referred by single-cell analysis to differential clonal transcriptomic, epigenomic, and histopathologic signatures [36].…”

Section: Discussionsupporting

confidence: 93%

“…Our data reveal regional alterations and tumour heterogeneity in two cases (one atypical and the other anaplastic), in agreement with previous studies in the literature [35,36], that the biological behaviour could explain. Recently, a spatial heterogeneity at molecular and radiographic level has been referred by single-cell analysis to differential clonal transcriptomic, epigenomic, and histopathologic signatures [36]. Interestingly, pTERT mutations are adverse prognostic factors in terms of OS in the overall group of malignant meningiomas and, more significantly, in the sub-group of anaplastic tumours.…”

Section: Discussionsupporting

confidence: 93%

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Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas

et al. 2021

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Background: The role of telomerase reverse transcriptase (TERT) gene promoter mutations (pTERT) in atypical and anaplastic meningiomas remains controversial. This study aimed to evaluate their impact on the histologic diagnosis and prognosis in a retrospective series of 74 patients with atypical and anaplastic meningioma, including disease progression and relapse. A supplementary panel of 21 benign tumours was used as a control cohort. Materials and Methods: The mutation rate of the pTERT gene was assessed by Sanger sequencing. ATRX protein expression was detected by immunohistochemistry. The phenotypic and genotypic intra-tumour heterogeneity was studied in a sub-group of 12 cases using a Molecular Machines & Industries (MMI) CellCut laser microdissection (LMD) system. Results: pTERT mutations were detected in 12/74 (17.6%) malignant meningiomas. The mutation rate was significantly higher in anaplastic meningiomas (7/23, 30.4%) compared to atypical tumours (5/48, 10.4%) (p = 0.0443). In contrast, the mutation rate was < 5% in benign tumours. All pTERT mutant cases retained nuclear ATRX immunoreactivity. pTERT mutations were significantly associated with the histologic grade (p = 0.0443) and were adverse prognostic factors for anaplastic tumours (p = 0.06). Conclusion: We reported on the pTERT mutation spectrum in malignant meningiomas, supporting their use in the prognostic classification.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas

et al. 2021

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“…3e). Moreover, analysis of our previously reported DNA methylation profiles on 86 spatially distinct meningioma samples from 13 tumors 23 revealed 92% of samples classified in concordance with the consensus epigenetic group of each tumor (Extended Data Fig. 5d).…”

Section: Group B Meningiomas Are Immune-enrichedmentioning

confidence: 67%

Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

Raleigh

Magill

Eaton

et al. 2020

Preprint

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Meningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function of NF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.

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“…Similarly, Magil et al have recently applied a CRISPR-Cas interference-based approach in brain cancer organoids [ 81 ]. Particularly, they generated meningioma cells expressing a specific Cas9 from patients’ tumor samples and co-cultured them with brain organoids.…”

Section: Overcoming Challenges With Possible Technical Solutionsmentioning

confidence: 99%

Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids

Costamagna

Comi

Corti

2021

IJMS

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In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson’s disease, and Alzheimer’s disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders.

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Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma

Cited by 59 publications

References 84 publications

Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas

Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas

Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids

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