Ganesh M Shankar1,2,3,4,5, Malak Abedalthagafi3,6,7,8, Rachael A Vaubel9, Parker H Merrill6, Naema Nayyar4,5, Corey M Gill4,5, Ryan Brewster6, Wenya Linda Bi10, Pankaj K Agarwalla11, Aaron R Thorner12,13, David A Reardon3,12,14, Ossama Al-Mefty3,10, Patrick Y Wen3,12,14, Brian M Alexander3,15, Paul van Hummelen12,13, Tracy T Batchelor3,4,5, Keith L Ligon3,5,12, Azra H Ligon3,6,16, Matthew Meyerson2,3,12,13, Ian F Dunn3,10,14, Rameen Beroukhim3,6,12,14, David N Louis3,5,17, Arie Perry18, Scott L Carter3,19,20, Caterina Giannini9, William T Curry3,5,11, Daniel P Cahill3,5,11, Frederick G Barker3,5,11, Priscilla K Brastianos1,2,3,4,5, Sandro Santagata3,6,21,22. 1. Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. 2. Broad Institute of MIT and Harvard, Boston, Massachusetts, USA. 3. Harvard Medical School, Boston, Massachusetts, USA. 4. Division of Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. 5. Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA. 6. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. 7. Department of Pathology, King Fahad Medical City, Riyadh, Saudi Arabia. 8. King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. 9. Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA. 10. Department of Neurosurgery, Brigham and Hospital, Boston, Massachusetts, USA. 11. Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA. 12. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 13. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 14. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. 15. Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA. 16. Clinical Cytogenetics Laboratory, Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, Massachusetts, USA. 17. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. 18. Department of Pathology and Neurological Surgery, University of California-San Francisco, San Francisco, California, USA. 19. Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 20. Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 21. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 22. Ludwig Center at Harvard, Boston, Massachusetts, USA.
Abstract
Background: 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. Methods: 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. Results: 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. Conclusion: 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.
Background: 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. Methods: 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. Results: 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 BAP1cancer predisposition syndrome. Conclusion: 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.
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