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Tumor Suppressor Gene PBRM1 Frequently Inactivated in Papillary Meningioma

Key findings

  • As part of a comprehensive genomic profiling initiative, researchers at Massachusetts General Hospital analyzed 562 meningiomas, including eight with >50% papillary morphology and 22 with focal papillary features
  • Three of the papillary meningiomas and eight of the focal papillary meningiomas exhibited inactivation of a tumor suppressor gene, PBRM1
  • Five additional meningiomas had inactivating alterations in PBRM1 but did not display overt papillary morphology; thus, 11 of 16 PBRM1-mutant cases (69%) occurred in meningiomas with papillary features (P < 0.0001)
  • Inclusion of patients with PBRM1-mutant tumors in clinical trials may lead to the development of new therapies for papillary meningioma

Aggressive meningiomas often display either rhabdoid or papillary morphology upon microscopic histology examination. Rhabdoid meningioma typically harbors mutations in BAP1, but the genetic alterations associated with papillary meningioma are unclear. Both of these cancer subtypes are malignant and aggressive.

Neurosurgeons Tareq A. Juratli, MD, in the Department of Neurosurgery at Carl Gustav Carus University, Dresden, Germany, and Daniel P. Cahill, MD, PhD, in the Department of Neurosurgery at Massachusetts General Hospital and neurosurgical oncologist at the Mass General Cancer Center, and colleagues recently determined that a tumor suppressor gene, PBRM1, is mutated in rare but aggressive papillary meningiomas. In a letter to the editor of Acta Neuropathologica, they explain the clinical implications of their findings.

Study Design

Because papillary meningioma is rare, the researchers mined data collected as part of a comprehensive genomic profiling initiative. They analyzed 562 meningiomas representing a general population of all World Health Organization grades. There were eight papillary meningiomas (>50% papillary morphology) and 22 meningiomas with focal papillary features (10%–50%).

PBRM1 Altertions

  • Two papillary meningiomas exhibited a truncating mutation in PBRM1 and one had a homozygous deletion of PBRM1
  • Eight of the focal papillary meningiomas were PBRM1-mutant
  • An additional five of the 562 meningiomas had inactivating alterations in PBRM1, but did not display overt papillary morphology

Thus, 11 of 16 PBRM1-mutant meningiomas (69%) had papillary features (P < 0.0001). All 16 cases showed biallelic inactivation of PBRM1.

Overlap Between PBRM1 and BAP1 Mutations

Five meningiomas had both PBRM1 mutations and BAP1 mutations. Three of these cases displayed papillary features and two had rhabdoid features.

In the cohort of 562 meningiomas:

  • 13 of 17 rhabdoid meningiomas were BAP1-mutant/PBRM1–wild type (wt)
  • Two of 19 papillary meningiomas were BAP1-mutant/PBRM1–wt
  • Seven of 11 BAP1-wt/PBRM1-mutant meningiomas had papillary morphology

Looking Ahead

Although the PBRM1 mutation seems to be uncommon in meningioma, the inclusion of patients with this defined genetic subtype in clinical trials may lead to new therapeutic approaches. For example, in patients with clear-cell renal cell carcinoma, a study published in Science found that tumors harboring inactivating PBRM1 mutations were more likely to respond to an immune checkpoint inhibitor.

Further studies will presumably also determine whether PBRM1 mutation is an independent negative prognostic biomarker.

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

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