Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas

Ganesh M. Shankar, Malak Abedalthagafi, Rachael A. Vaubel, Parker H. Merrill, Naema Nayyar, Corey M. Gill, Ryan Brewster, Wenya Linda Bi, Pankaj K. Agarwalla, Aaron R. Thorner, David A. Reardon, Ossama Al-Mefty, Patrick Y. Wen, Brian M. Alexander, Paul Van Hummelen, Tracy T. Batchelor, Keith L. Ligon, Azra H. Ligon, Matthew Meyerson, Ian F. Dunn & 10 others Rameen Beroukhim, David N. Louis, Arie Perry, Scott L. Carter, Caterina Giannini, William T. Curry, Daniel P. Cahill, Frederick G. Barker, Priscilla K. Brastianos, Sandro Santagata

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)535-545
Number of pages11
JournalNeuro-Oncology
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2017

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Meningioma
Mutation
Proteins
Neoplasms
Ubiquitin Thiolesterase
BRCA1 Protein
Recurrence
Observer Variation
Neoplasm Genes
Kaplan-Meier Estimate
Ubiquitin
Tumor Suppressor Genes
Immunohistochemistry

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Shankar, G. M., Abedalthagafi, M., Vaubel, R. A., Merrill, P. H., Nayyar, N., Gill, C. M., ... Santagata, S. (2017). Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro-Oncology, 19(4), 535-545. https://doi.org/10.1093/neuonc/now235

Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. / Shankar, Ganesh M.; Abedalthagafi, Malak; Vaubel, Rachael A.; Merrill, Parker H.; Nayyar, Naema; Gill, Corey M.; Brewster, Ryan; Bi, Wenya Linda; Agarwalla, Pankaj K.; Thorner, Aaron R.; Reardon, David A.; Al-Mefty, Ossama; Wen, Patrick Y.; Alexander, Brian M.; Van Hummelen, Paul; Batchelor, Tracy T.; Ligon, Keith L.; Ligon, Azra H.; Meyerson, Matthew; Dunn, Ian F.; Beroukhim, Rameen; Louis, David N.; Perry, Arie; Carter, Scott L.; Giannini, Caterina; Curry, William T.; Cahill, Daniel P.; Barker, Frederick G.; Brastianos, Priscilla K.; Santagata, Sandro.

In: Neuro-Oncology, Vol. 19, No. 4, 01.04.2017, p. 535-545.

Research output: Contribution to journalArticle

Shankar, GM, Abedalthagafi, M, Vaubel, RA, Merrill, PH, Nayyar, N, Gill, CM, Brewster, R, Bi, WL, Agarwalla, PK, Thorner, AR, Reardon, DA, Al-Mefty, O, Wen, PY, Alexander, BM, Van Hummelen, P, Batchelor, TT, Ligon, KL, Ligon, AH, Meyerson, M, Dunn, IF, Beroukhim, R, Louis, DN, Perry, A, Carter, SL, Giannini, C, Curry, WT, Cahill, DP, Barker, FG, Brastianos, PK & Santagata, S 2017, 'Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas', Neuro-Oncology, vol. 19, no. 4, pp. 535-545. https://doi.org/10.1093/neuonc/now235
Shankar GM, Abedalthagafi M, Vaubel RA, Merrill PH, Nayyar N, Gill CM et al. Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro-Oncology. 2017 Apr 1;19(4):535-545. https://doi.org/10.1093/neuonc/now235
Shankar, Ganesh M. ; Abedalthagafi, Malak ; Vaubel, Rachael A. ; Merrill, Parker H. ; Nayyar, Naema ; Gill, Corey M. ; Brewster, Ryan ; Bi, Wenya Linda ; Agarwalla, Pankaj K. ; Thorner, Aaron R. ; Reardon, David A. ; Al-Mefty, Ossama ; Wen, Patrick Y. ; Alexander, Brian M. ; Van Hummelen, Paul ; Batchelor, Tracy T. ; Ligon, Keith L. ; Ligon, Azra H. ; Meyerson, Matthew ; Dunn, Ian F. ; Beroukhim, Rameen ; Louis, David N. ; Perry, Arie ; Carter, Scott L. ; Giannini, Caterina ; Curry, William T. ; Cahill, Daniel P. ; Barker, Frederick G. ; Brastianos, Priscilla K. ; Santagata, Sandro. / Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. In: Neuro-Oncology. 2017 ; Vol. 19, No. 4. pp. 535-545.
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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.",
author = "Shankar, {Ganesh M.} and Malak Abedalthagafi and Vaubel, {Rachael A.} and Merrill, {Parker H.} and Naema Nayyar and Gill, {Corey M.} and Ryan Brewster and Bi, {Wenya Linda} and Agarwalla, {Pankaj K.} and Thorner, {Aaron R.} and Reardon, {David A.} and Ossama Al-Mefty and Wen, {Patrick Y.} and Alexander, {Brian M.} and {Van Hummelen}, Paul and Batchelor, {Tracy T.} and Ligon, {Keith L.} and Ligon, {Azra H.} and Matthew Meyerson and Dunn, {Ian F.} and Rameen Beroukhim and Louis, {David N.} and Arie Perry and Carter, {Scott L.} and Caterina Giannini and Curry, {William T.} and Cahill, {Daniel P.} and Barker, {Frederick G.} and Brastianos, {Priscilla K.} and Sandro Santagata",
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T1 - Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas

AU - Shankar, Ganesh M.

AU - Abedalthagafi, Malak

AU - Vaubel, Rachael A.

AU - Merrill, Parker H.

AU - Nayyar, Naema

AU - Gill, Corey M.

AU - Brewster, Ryan

AU - Bi, Wenya Linda

AU - Agarwalla, Pankaj K.

AU - Thorner, Aaron R.

AU - Reardon, David A.

AU - Al-Mefty, Ossama

AU - Wen, Patrick Y.

AU - Alexander, Brian M.

AU - Van Hummelen, Paul

AU - Batchelor, Tracy T.

AU - Ligon, Keith L.

AU - Ligon, Azra H.

AU - Meyerson, Matthew

AU - Dunn, Ian F.

AU - Beroukhim, Rameen

AU - Louis, David N.

AU - Perry, Arie

AU - Carter, Scott L.

AU - Giannini, Caterina

AU - Curry, William T.

AU - Cahill, Daniel P.

AU - Barker, Frederick G.

AU - Brastianos, Priscilla K.

AU - Santagata, Sandro

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

AB - 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.

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