The Meningioma Enhancer Landscape Delineates Novel Subgroups and Drives Druggable Dependencies

Prager, Briana C.; Vasudevan, Harish N.; Dixit, Deobrat; Bernatchez, Jean A.; Wu, Qiulian; Wallace, Lisa C.; Bhargava, Shruti; Lee, Derrick; King, Bradley H.; Morton, Andrew; Gimple, Ryan C.; Pekmezci, Melike; Zhu, Zhe; Siqueira-Neto, Jair L.; Wang, Xiuxing; Xie, Qi; Chen, Clark; Barnett, Gene H.; Vogelbaum, Michael A.; Mack, Stephen C.; Chávez, Lukas; Perry, Arie; Raleigh, David R.; Rich, Jeremy

doi:10.1158/2159-8290.cd-20-0160

Cited by 36 publications

(33 citation statements)

References 73 publications

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“…However, the identification of Hh‐activated meningiomas is hindered by the heterogeneity of causal mechanisms. Variable mutations in SMO , SUFU and PRKAR1A were described, and Hh pathway activation was also highlighted independently from somatic mutation within the pathway 25 …”

Section: Discussionmentioning

confidence: 99%

GAB1 overexpression identifies hedgehog‐activated anterior skull base meningiomas

Boetto

Lerond

Peyre

et al. 2021

Neuropathology Appl Neurobio

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Aims Mutations activating the hedgehog (Hh) signalling pathway have been described in anterior skull base meningiomas, raising hope for the use of targeted therapies. However, identification of Hh‐activated tumours is hampered by the lack of a reliable immunohistochemical marker. We report the evaluation of GAB1, an immunohistochemical marker used to detect Hh pathway activation in medulloblastoma, as a potential marker of Hh‐activated meningiomas. Methods GAB1 staining was compared to SMO mutation detection with Sanger and NGS techniques as well as Hh pathway activation study through mRNA expression level analyses in a discovery set of 110 anterior skull base meningiomas and in a prospective validation set of 21 meningiomas. Results Using an expression score ranging from 0 to 400, we show that a cut‐off score of 250 lead to excellent detection of Hh pathway mutations (sensitivity 100%, specificity 86%). The prospective validation set confirmed the excellent negative predictive value of GAB1 to exclude Hh‐independent meningiomas. We describe a large series of 32 SMO‐mutant meningiomas and define multiple ways of Hh activation, either through somatic mutations or associated with mutually co‐exclusive sonic hedgehog (SHH) or Indian hedgehog (IHH) overexpression independent of the mutations. Conclusion The assessment of GAB1 expression by an immunohistochemical score is a fast and cost‐efficient tool to screen anterior skull base meningiomas for activation of the Hh pathway. It could facilitate the identification of selected cases amenable to sequencing for Hh pathway genes as predictive markers for targeted therapy.

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Section: Discussionmentioning

confidence: 99%

GAB1 overexpression identifies hedgehog‐activated anterior skull base meningiomas

Boetto

Lerond

Peyre

et al. 2021

Neuropathology Appl Neurobio

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“…For instance, the simultaneous targeting of BRD4 (by BETi) and oncogenic pathways, such as WNT and MAPK, in CRC inhibits the oncogenic expression of MYC and decreases the risk of tumour resistance [ 141 ]. For this aim, it is important to identify the dependency on key TFs by interrogating the landscape of active enhancers in tumour cells [ 142 , 143 ]. Profiling active enhancers was recently applied in meningioma, and it could not only stratify different tumour subtypes, but also proposed druggable enhancers and their dependencies on upstream signalling pathways [ 142 ].…”

Section: Cancer-related Genetic Variations At Enhancersmentioning

confidence: 99%

“…For this aim, it is important to identify the dependency on key TFs by interrogating the landscape of active enhancers in tumour cells [ 142 , 143 ]. Profiling active enhancers was recently applied in meningioma, and it could not only stratify different tumour subtypes, but also proposed druggable enhancers and their dependencies on upstream signalling pathways [ 142 ]. The efficacy of co-inhibition strategies is more evident in tumours with hormonal dependencies.…”

Section: Cancer-related Genetic Variations At Enhancersmentioning

confidence: 99%

Deregulation of Transcriptional Enhancers in Cancer

Azad

Atlasi

2021

Cancers

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Epigenetic regulations can shape a cell’s identity by reversible modifications of the chromatin that ultimately control gene expression in response to internal and external cues. In this review, we first discuss the concept of cell plasticity in cancer, a process that is directly controlled by epigenetic mechanisms, with a particular focus on transcriptional enhancers as the cornerstone of epigenetic regulation. In the second part, we discuss mechanisms of enhancer deregulation in adult stem cells and epithelial-to-mesenchymal transition (EMT), as two paradigms of cell plasticity that are dependent on epigenetic regulation and serve as major sources of tumour heterogeneity. Finally, we review how genetic variations at enhancers and their epigenetic modifiers contribute to tumourigenesis, and we highlight examples of cancer drugs that target epigenetic modifications at enhancers.

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“…4c, d ). To define FOXM1 targets in meningioma, differentially expressed genes with FOXM1 binding motifs were analyzed in our previously reported matched RNA sequencing, H3K27ac ChIP sequencing, and DNA methylation profiling on 25 meningiomas (15 Hypermitotic, 10 non-Hypermitotic) 43 . FOXM1 target genes in Hypermitotic meningiomas regulated the DNA damage response, the cell cycle, and tumor metabolism ( Extended Data Fig.…”

Section: Main Textmentioning

confidence: 99%

Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

Choudhury¹,

Magill²,

Eaton³

et al. 2020

Preprint

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SUMMARYMeningiomas 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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The Meningioma Enhancer Landscape Delineates Novel Subgroups and Drives Druggable Dependencies

Cited by 36 publications

References 73 publications

GAB1 overexpression identifies hedgehog‐activated anterior skull base meningiomas

GAB1 overexpression identifies hedgehog‐activated anterior skull base meningiomas

Deregulation of Transcriptional Enhancers in Cancer

Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

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