title: The genomic landscape of schwannoma.
abstract: Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Jalali
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wilson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Arnavaz
authors.initials: A
authors.lastname: Danesh
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mira
authors.initials: M
authors.lastname: Li
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Klironomos
authors.affiliation: SPARC Biocentre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Krieger
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Alireza
authors.initials: A
authors.lastname: Mansouri
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Osaama
authors.initials: O
authors.lastname: Khan
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Mamatjan
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Landon-Brace
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Takyee
authors.initials: T
authors.lastname: Tung
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Dowar
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Li
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Bruce
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Burrell
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Tonge
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Amir
authors.identifier: 0000-0002-4275-9715
authors.initials: A
authors.lastname: Alamsahebpour
authors.affiliation: Department of Neurosurgery, University Hospital of Cologne, Cologne Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Krischek
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Pankaj Kumar
authors.initials: PK
authors.lastname: Agarwalla
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Wenya Linda
authors.initials: WL
authors.lastname: Bi
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.|Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Dunn
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Department of Neurosurgery, University Health Network, Toronto, Ontario, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
authors.affiliation: Department of Medicine (Neurology), and the Elizabeth Raab Neurofibromatosis Program, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vera
authors.initials: V
authors.lastname: Bril
authors.affiliation: Department of Science and Technology, Università degli Studi del Sannio, Benevento, Italy.|Department of Pathology and Cell Biology and Neurology, Columbia University, New York, New York, USA.
authors.forename: Stefano M
authors.identifier: 0000-0002-8298-9777
authors.initials: SM
authors.lastname: Pagnotta
authors.affiliation: Department of Pathology and Cell Biology and Neurology, Columbia University, New York, New York, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Department of Pathology, Maryland Anderson Cancer Center, Houston, Texas, USA.|Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Neurosurgery, University Health Network, Toronto, Ontario, Canada.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D004428:Ear Neoplasms / Q000235:genetics*; D059472:Exome; D005260:Female; D050939:Gene Fusion; D015894:Genome, Human; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009442:Neurilemmoma / Q000235:genetics*; D012334:RNA, Neoplasm; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D012697:Serine Endopeptidases / Q000235:genetics; D013125:Spinal Neoplasms / Q000235:genetics*; D014722:Vestibule, Labyrinth
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; C478582:SH3PXD2A protein, human; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases