Related Experiment Video
Updated: Sep 24, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities
Abrar Choudhury1,2,3,4, Stephen T Magill5, Charlotte D Eaton1,2
1Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA.
Abstract:
Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.
Insights
Meningiomas, common brain tumors, are classified into three DNA methylation groups with distinct outcomes. This research identifies new therapeutic vulnerabilities and strategies for these tumor types.
Area of Science:
- Neuro-oncology
- Genomics
- Translational Medicine
Background:
- Meningiomas are the most common primary intracranial tumors.
- Current medical therapies for meningiomas are limited due to a poor understanding of their underlying biology.
Purpose of the Study:
- To classify meningiomas based on molecular characteristics.
- To identify distinct clinical outcomes, biological drivers, and therapeutic vulnerabilities within meningioma subtypes.
- To translate molecular findings into potential clinical treatments.
Main Methods:
- DNA methylation profiling of 565 meningiomas.
- Integration of genetic, transcriptomic, biochemical, proteomic, and single-cell analyses.
- Validation of therapeutic strategies using cell culture, organoids, xenografts, and patient data.
Main Results:
- Identified three distinct DNA methylation groups: Merlin-intact (34%, best outcome), Immune-enriched (38%, intermediate outcome), and Hypermitotic (28%, worst outcome).
- Merlin-intact meningiomas show susceptibility to cytotoxic therapy.
- Immune-enriched meningiomas are characterized by immune infiltration and lymphatic vessels.
- Hypermitotic meningiomas exhibit cell cycle dysregulation and resistance to cytotoxic therapy.
Conclusions:
- DNA methylation profiling provides a robust classification of meningiomas with distinct clinical trajectories.
- Understanding these molecular subtypes reveals specific therapeutic vulnerabilities.
- Cytostatic cell cycle inhibitors show promise in attenuating meningioma growth across preclinical models and patients.
Related Concept Videos
01:46Epigenetic Regulation
01:17Phase II Reactions: Methylation Reactions
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...