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Categories of Genomic Profiles of Aggressive Meningiomas to Facilitate Drug Development

Key findings

  • Massachusetts General Hospital researchers genomically profiled 850 high-grade/progressive meningiomas and detected three distinct patterns
  • The "canonical" group had mutations in NF2 and other previously reported genes; about 20% of NF2-mutant aggressive meningiomas had alterations of genes encoding regulators of CDK pathway and thus might respond to CDK4/CDK6 inhibitors
  • The "NF2-agnostic" group contained both NF2-mutant and wild-type tumors and were typified by poor-prognostic TERT promoter or TP53 mutations
  • The final group was essentially exclusive of NF2 mutations and itself contained three subgroups
  • Molecular subclassification of aggressive meningiomas should allow identification of patients who are good candidates for trials of targeted therapies

There is substantial heterogeneity in the clinical presentation of meningiomas. Some are initially benign grade 1 disease and recur or transform to a higher grade only after many years. Others are grade 2 or 3 at the initial presentation. Predictors of recurrence and malignant transformation would help clinicians by indicating when intensified radiation, radical surgery or targeted therapy is suitable.

So far, it's known that high-grade meningiomas are often characterized by inactivation of the NF2 tumor suppressor gene. Evidence is accumulating about other genes, but those are altered in <35% of aggressive meningiomas, suggesting there must be additional mutations in unidentified or underrepresented genes.

Pathologist Erik A. Williams, MD, neurosurgeon Tareq A. Juratli, MDDaniel P. Cahill, MD, PhD, principal investigator of the Translational Neuro-Oncology Laboratory, and neurosurgeon in the Department of Neurosurgery  at Massachusetts General Hospital, Shakti H. Ramkissoon, MD, PhD, MMSc, of the Wake Forest School of Medicine and colleagues recently performed comprehensive genomic profiling of the largest collection of high-grade/progressive meningiomas to date. In Acta Neuropathologica Communications, they report three distinct patterns that might identify patients who are good candidates for various targeted treatments.

Study Sample

Between 2013 and 2019, the researchers used a next-generation sequencing panel to analyze 405 cancer-related genes in meningiomas from 850 patients. The World Health Organization grades were:

  • Grade 3: 176 meningiomas
  • Grade 2: 441
  • Grade 1 but progressive: 220
  • Grade unavailable: 13


The first group of meningiomas was the most common, representing 50% of cases. It was termed "canonical" because mutations occurred in NF2 and other previously reported genes.

Alterations of genes encoding regulators of the cyclin-dependent kinase pathway occurred in about 20% of NF2-mutant high-grade/progressive meningiomas. This is clinically relevant because CDK4/CDK6 inhibitors are already approved for treating breast cancer and are in genomically guided trials for other tumor types.


The second group (10% of cases) contained both NF2-mutant and wild-type tumors. Recurrent mutations in the TERT promoter were detected in a substantial fraction, ranging from 2.5% of grade 1 tumors to 14% of grade 3.

This group also included high-grade meningiomas that harbored mutations in the TP53 oncogene, which has seldom been described previously in meningiomas. Both of these mutations are generally associated with poor cancer prognosis, so this group may prove difficult to treat with targeted agents.


The final group, which the researchers divided into three subgroups, essentially excluded NF2 mutations:

  • The first subgroup (5% of cases) was characterized by mutations in BAP1 and/or PBRM1. Inactivation of BAP1, a tumor suppressor gene, has been linked to aggressive meningiomas with rhabdoid features, a poor prognostic sign. PBRM1 mutations have been linked to papillary features
  • The second subgroup (5% of cases) consisted of skull-base meningiomas with AKT1SMO or PIK3CA mutations. These mutations were usually present in grade 1 tumors, but since they were also present in high-grade/progressive meningiomas, they may not exclusively indicate non-aggressive behavior
  • The last subgroup (30% of cases) had heterogeneous mutations but none in NF2TERT promoter, TP53, BAP1, PBRM1, AKT1SMO or PIK3CA. Chromosome 22 monosomy was present in half of these cases and was linked to a higher grade

Looking Ahead

Medulloblastomas, gliomas and other central nervous system tumors are now defined by molecular characteristics in addition to histology. Similarly, molecular subclassification of meningiomas should allow more precise diagnosis and identify patients who are good candidates for trials of targeted therapies.

Learn more about the Stephen E. and Catherine Pappas Center for Neuro-Oncology

Refer a patient to Mass General Neurosurgery


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