title: Evidence of polyclonality in neurofibromatosis type 2-associated multilobulated vestibular schwannomas.
abstract: BACKGROUND
  Neurofibromatosis type 2 (NF2) is a tumor syndrome that results from mutation of the NF2 tumor suppressor gene. The hallmark of NF2 is the presence of bilateral vestibular schwannoma (VS). Though NF2-associated and sporadic VS share identical histopathologic findings and cytogenetic alterations, NF2-associated VS often appears multilobulated, is less responsive to radiosurgery, and has worse surgical outcomes. Temporal bone autopsy specimens and MRI of the inner ear performed on NF2 patients suggest that multiple discrete tumors may be present within the labyrinth and cerebellopontine angle.
  
  
  METHODS
  Treatment-naïve ears in patients enrolled in a prospective NF2 natural history study (NIH#08-N-0044) were included for MRI analysis. T2-weighted and postcontrast T1-weighted MRIs were evaluated for the presence of multiple discrete tumors or a multilobulated mass. Peripheral blood (germline) and regional samples of tumor tissue were procured from consecutive patients enrolled in this study undergoing resection of a multilobulated VS (MVS). Histopathologic evaluation and genetic analysis (single nucleotide polymorphism array analysis, NF2 sequencing) were performed on each specimen.
  
  
  RESULTS
  Over half of NF2 ears harbored either an MVS (60/139 ears) or multiple discrete masses (19/139 ears). For 4 successive MVSs, genetic analysis revealed an admixture of cell populations, each with its own somatic NF2 mutation or deletion.
  
  
  CONCLUSIONS
  These findings suggest that the majority of NF2-associated VSs are polyclonal, such that the tumor mass represents a collision of multiple, distinct tumor clones. This explains the characteristic lobulated gross appearance of NF2-associated VS, and may also explain the substantially different treatment outcomes compared with sporadic VS.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Ramita
authors.initials: R
authors.lastname: Dewan
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Alex
authors.initials: A
authors.lastname: Pemov
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: H Jeffrey
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Keaton L
authors.initials: KL
authors.lastname: Morgan
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Raul A
authors.initials: RA
authors.lastname: Vasquez
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Prashant
authors.initials: P
authors.lastname: Chittiboina
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Settara C
authors.initials: SC
authors.lastname: Chandrasekharappa
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Abhik
authors.initials: A
authors.lastname: Ray-Chaudhury
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: John A
authors.initials: JA
authors.lastname: Butman
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Stewart
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.D., K.L.M., R.A.V., P.C., X.W., A.R.-C., A.R.A.); Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (A.P., D.R.S.); Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (H.J.K.); Radiology and Imaging Sciences, The Clinical Center at the National Institutes of Health, National Institutes of Health, Bethesda, Maryland (J.A.B.); Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (S.C.C.); Department of Neurosurgery, University of Virginia, CDW, Charlottesville, Virginia (A.R.A.).
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Asthagiri
mesh_terms: D004423:Ear / Q000473:pathology; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D008279:Magnetic Resonance Imaging; D009154:Mutation; D016518:Neurofibromatosis 2 / Q000235:genetics* / Q000473:pathology*; D009464:Neuroma, Acoustic / Q000235:genetics* / Q000473:pathology*
keywords: NF2 gene; Sanger sequencing; clonality; multilobulated vestibular schwannoma; single nucleotide polymorphism