title: Molecular Analysis of Hybrid Neurofibroma/Schwannoma Identifies Common Monosomy 22 and α-T-Catenin/CTNNA3 as a Novel Candidate Tumor Suppressor.
abstract: Neurofibromas and schwannomas are benign Schwann cell-derived peripheral nerve sheath tumors arising sporadically and within neurofibromatoses. Multiple tumors are a hallmark of neurofibromatosis type 1 (NF1) and type 2 (NF2) and schwannomatosis. Neurofibromas in NF1 and schwannomas in NF2 or schwannomatosis are defined by distinctive molecular hits. Among these, multiple hybrid neurofibromas/schwannomas may also appear, not yet being defined by a molecular background. We therefore performed molecular analysis of 22 hybrid neurofibromas/schwannomas using array comparative genomic hybridization, immunohistochemistry, quantitative RT-PCR, and functional analyses of cultured Schwann cells. Furthermore, we analyzed SMARCB1 by fluorescence in situ hybridization and multiplex ligation-dependent probe. Monosomy 22 was identified in 44% of tumors of tested patients with hybrid neurofibromas/schwannomas. In addition, in a single case, we detected focal deletion of the α-T-catenin/CTNNA3 gene (10q21.3). To further characterize this candidate, transient knockdown of α-T-catenin in Schwann cells was performed. CTNNA3 depleted cells showed cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like abnormalities. To conclude, we uncovered loss of chromosome 22 in almost half of all cases with hybrid neurofibromas/schwannomas of patients with multiple peripheral nerve sheath tumors. We tagged α-T-catenin/CTNNA3 as a novel candidate gene. Our functional investigations might indicate involvement of α-T-catenin/CTNNA3 in the biology of peripheral nerve sheath tumors.
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Stahn
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Nagel
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Fischer-Huchzermeyer
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Oyen
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gesk
authors.affiliation: Institute of Human Genetics, University Hospital Münster, Münster, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Bohring
authors.affiliation: Department of Sleep Medicine and Neuromuscular Disorders, University Hospital Münster, Münster, Germany.
authors.forename: Levan
authors.initials: L
authors.lastname: Chikobava
authors.affiliation: Department of Sleep Medicine and Neuromuscular Disorders, University Hospital Münster, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Young
authors.affiliation: Institute of Pathology, Health Care Center, Brandenburg Hospital, Brandenburg Medical School Theodor Fontane, Brandenburg an der Havel, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Gess
authors.affiliation: Institute of Pathology, HELIOS Klinikum Emil von Behring, Berlin, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Werner
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Senner
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany; Institute of Pathology, Health Care Center, Brandenburg Hospital, Brandenburg Medical School Theodor Fontane, Brandenburg an der Havel, Germany. Electronic address: anja.harder@ukmuenster.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Harder
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009006:Monosomy; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000473:pathology; D009442:Neurilemmoma / Q000235:genetics* / Q000473:pathology; D009455:Neurofibroma / Q000235:genetics* / Q000473:pathology; D017253:Neurofibromatoses / Q000235:genetics* / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult; D051178:alpha Catenin / Q000235:genetics*
chemical_list: C441963:CTNNA3 protein, human; D025521:Tumor Suppressor Proteins; D051178:alpha Catenin