Hypermitotic meningiomas harbor DNA methylation subgroups with distinct biological and clinical features

Neuro-Oncology, vol. 25, pp. 520–530

Abstract

BACKGROUND: Meningiomas, the most common primary intracranial tumors, can be separated into 3 DNA methylation groups with distinct biological drivers, clinical outcomes, and therapeutic vulnerabilities. Alternative meningioma grouping schemes using copy number variants, gene expression profiles, somatic short variants, or integrated molecular models have been proposed. These data suggest meningioma DNA methylation groups may harbor subgroups unifying contrasting theories of meningioma biology. METHODS: A total of 565 meningioma DNA methylation profiles from patients with comprehensive clinical follow-up at independent discovery (n = 200) or validation (n = 365) institutions were reanalyzed and classified into Merlin-intact, Immune-enriched, or Hypermitotic DNA methylation groups. RNA sequencing from the discovery (n = 200) or validation (n = 302) cohort were analyzed in the context of DNA methylation groups to identify subgroups. Biological features and clinical outcomes were analyzed across meningioma grouping schemes. RESULTS: RNA sequencing revealed differential enrichment of FOXM1 target genes across two subgroups of Hypermitotic meningiomas. Differential expression and ontology analyses showed the subgroup of Hypermitotic meningiomas without FOXM1 target gene enrichment was distinguished by gene expression programs driving macromolecular metabolism. Analysis of genetic, epigenetic, gene expression, or cellular features revealed Hypermitotic meningioma subgroups were concordant with Proliferative or Hypermetabolic meningiomas, which were previously reported alongside Merlin-intact and Immune-enriched tumors using an integrated molecular model. The addition of DNA methylation subgroups to clinical models refined the prediction of postoperative outcomes compared to the addition of DNA methylation groups. CONCLUSIONS: Meningiomas can be separated into three DNA methylation groups and Hypermitotic meningiomas can be subdivided into Proliferative and Hypermetabolic subgroups, each with distinct biological and clinical features.

Authors 14

1. Abrar Choudhury

   University of California, San Francisco

   Affiliation as printed

   Departments of Radiation Oncology and Neurological Surgery, University of California San Francisco , San Francisco, CA , USA

2. William C. Chen

   University of California, San Francisco

   Affiliation as printed

   Departments of Radiation Oncology and Neurological Surgery, University of California San Francisco , San Francisco, CA , USA

3. Calixto‐Hope G. Lucas

   University of California, San Francisco

   Affiliation as printed

   Department of Pathology, University of California San Francisco , San Francisco, CA , USA

   Departments of Radiation Oncology and Neurological Surgery, University of California San Francisco , San Francisco, CA , USA

4. James C. Bayley

   Baylor College of Medicine · Texas Children's Hospital

   Affiliation as printed

   Department of Neurosurgery, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital , Houston, TX , USA

5. Akdes Serin Harmancı

   Baylor College of Medicine · Texas Children's Hospital

   Affiliation as printed

   Department of Neurosurgery, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital , Houston, TX , USA

6. Sybren L. N. Maas Aachen Departments of Pathology Erasmus Medical Center

   Leiden University Medical Center · Erasmus MC

   Affiliation as printed

   Departments of Pathology, Leiden University Medical Center, Leiden, and Erasmus Medical Center , Rotterdam , The Netherlands

7. Sandro Santagata

   Brigham and Women's Hospital · Harvard University

   Affiliation as printed

   Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School , Boston, MA , USA

8. Tiemo Jürgen Klisch

   Baylor College of Medicine · Texas Children's Hospital

   Affiliation as printed

   Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital , Houston, TX , USA

9. Arie Perry

   University of California, San Francisco

   Affiliation as printed

   Department of Pathology, University of California San Francisco , San Francisco, CA , USA

10. Wenya Linda Bi

    Dana-Farber Cancer Institute

    Affiliation as printed

    Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA , USA

11. Felix Sahm

    German Cancer Research Center · Heidelberg University · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Department of Neuropathology, University Hospital Heidelberg and CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany

12. Akash J. Patel

    Baylor College of Medicine · Texas Children's Hospital

    Affiliation as printed

    Department of Neurosurgery, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital , Houston, TX , USA

13. Stephen T. Magill

    Northwestern University

    Affiliation as printed

    Department of Neurological Surgery, Northwestern University , Chicago, IL , USA

14. David Ronan Raleigh corresponding

    University of California, San Francisco

    Affiliation as printed

    Departments of Radiation Oncology and Neurological Surgery, University of California San Francisco , San Francisco, CA , USA