Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas.


Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making.


To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas.


The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome.


We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.

Shankar GM1,2,3,4,5, Abedalthagafi M3,6,7,8, Vaubel RA9, Merrill PH6, Nayyar N4,5, Gill CM4,5, Brewster R6, Bi WL10, Agarwalla PK11, Thorner AR12,13, Reardon DA3,12,14, Al-Mefty O3,10, Wen PY3,12,14, Alexander BM3,15, van Hummelen P12,13, Batchelor TT3,4,5, Ligon KL3,5,12, Ligon AH3,6,16, Meyerson M2,3,12,13, Dunn IF3,10,14, Beroukhim R3,6,12,14, Louis DN3,5,17, Perry A18, Carter SL3,19,20, Giannini C9, Curry WT Jr3,5,11, Cahill DP3,5,11, Barker FG 2nd3,5,11, Brastianos PK1,2,3,4,5, Santagata S3,6,21,22.

Neuro Oncol. 2017 Apr 1;19(4):535-545. doi: 10.1093/neuonc/now235.