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.
Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Division of Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Ganesh M
GM
Shankar
Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Pathology, King Fahad Medical City, Riyadh, Saudi Arabia.|King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
Malak
M
Abedalthagafi
Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Rachael A
RA
Vaubel
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Parker H
PH
Merrill
Division of Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Naema
N
Nayyar
Division of Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Corey M
CM
Gill
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Ryan
R
Brewster
Department of Neurosurgery, Brigham and Hospital, Boston, Massachusetts, USA.
Wenya Linda
WL
Bi
Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Pankaj K
PK
Agarwalla
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Aaron R
AR
Thorner
Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
David A
DA
Reardon
Harvard Medical School, Boston, Massachusetts, USA.|Department of Neurosurgery, Brigham and Hospital, Boston, Massachusetts, USA.
Ossama
O
Al-Mefty
Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Patrick Y
PY
Wen
Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA.
Brian M
BM
Alexander
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Paul
P
van Hummelen
Harvard Medical School, Boston, Massachusetts, USA.|Division of Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Tracy T
TT
Batchelor
Harvard Medical School, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Keith L
KL
Ligon
Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Clinical Cytogenetics Laboratory, Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Azra H
AH
Ligon
Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Matthew
M
Meyerson
Harvard Medical School, Boston, Massachusetts, USA.|Department of Neurosurgery, Brigham and Hospital, Boston, Massachusetts, USA.|Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Ian F
IF
Dunn
Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Rameen
R
Beroukhim
Harvard Medical School, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
David N
DN
Louis
Department of Pathology and Neurological Surgery, University of California-San Francisco, San Francisco, California, USA.
Arie
A
Perry
Harvard Medical School, Boston, Massachusetts, USA.|Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Scott L
SL
Carter
Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Caterina
C
Giannini
Harvard Medical School, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
William T
WT
Curry
Harvard Medical School, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Daniel P
DP
Cahill
Harvard Medical School, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Frederick G
FG
Barker
Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Division of Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.|Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Priscilla K
PK
Brastianos
Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Ludwig Center at Harvard, Boston, Massachusetts, USA.
Sandro
S
Santagata
D018450:Disease Progression; D018095:Germ-Line Mutation; D006801:Humans; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000473:pathology; D008579:Meningioma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D060787:Neoplasm Grading; D018335:Rhabdoid Tumor / Q000235:genetics* / Q000473:pathology; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
BAP1; exome sequencing; rhabdoid meningiomas