Comprehensive Molecular Profiling Identifies FOXM1 as a Key Transcription Factor for Meningioma Proliferation
Harish N. Vasudevan,
Steve E. Braunstein,
Joanna J. Phillips,
Melike Pekmezci,
Bryan A. Tomlin,
Ashley Wu,
Gerald F. Reis,
Stephen T. Magill,
Jie Zhang,
Felix Y. Feng,
Theodore Nicholaides,
Susan M. Chang,
Penny K. Sneed,
Michael W. McDermott,
Mitchel S. Berger,
Arie Perry,
David R. Raleigh
Affiliations
Harish N. Vasudevan
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
Steve E. Braunstein
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
Joanna J. Phillips
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
Melike Pekmezci
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA; Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA
Bryan A. Tomlin
Department of Economics, California State University Channel Islands, Camarillo, CA, USA
Ashley Wu
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
Gerald F. Reis
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
Stephen T. Magill
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
Jie Zhang
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
Felix Y. Feng
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
Theodore Nicholaides
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
Susan M. Chang
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
Penny K. Sneed
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
Michael W. McDermott
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
Mitchel S. Berger
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
Arie Perry
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
David R. Raleigh
Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Corresponding author
Summary: Meningioma is the most common primary intracranial tumor, but the molecular drivers of aggressive meningioma are incompletely understood. Using 280 human meningioma samples and RNA sequencing, immunohistochemistry, whole-exome sequencing, DNA methylation arrays, and targeted gene expression profiling, we comprehensively define the molecular profile of aggressive meningioma. Transcriptomic analyses identify FOXM1 as a key transcription factor for meningioma proliferation and a marker of poor clinical outcomes. Consistently, we discover genomic and epigenomic factors associated with FOXM1 activation in aggressive meningiomas. Finally, we define a FOXM1/Wnt signaling axis in meningioma that is associated with a mitotic gene expression program, poor clinical outcomes, and proliferation of primary meningioma cells. In summary, we find that multiple molecular mechanisms converge on a FOXM1/Wnt signaling axis in aggressive meningioma. : Using multiplatform molecular profiling, Vasudevan et al. comprehensively define the molecular profile of aggressive meningioma. They identify genomic, epigenomic, and transcriptomic mechanisms that converge on a FOXM1/Wnt signaling axis in aggressive meningioma that is associated with meningioma cell proliferation and is a marker of poor clinical outcomes across molecular subgroups. Keywords: DNA methylation, epigenome, FOXM1, genome, meningioma, NF2, RNA sequencing, transcriptome, whole-exome sequencing, Wnt
