title: Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas.
abstract: Schwannomas are benign nerve sheath tumors composed of well-differentiated Schwann cells. Other than frequent NF2 (neurofibromatosis type 2) mutations (50%-60%), their molecular pathogenesis is not fully understood. LATS1 and LATS2 are downstream molecules of NF2 and are negative regulators of the yes-associated protein (YAP) oncogene in the Hippo signaling pathway. We assessed mutations of the NF2, LATS1, and LATS2 genes, promoter methylation of LATS1 and LATS2, and expression of YAP and phosphorylated YAP in 82 cases of sporadic schwannomas. Targeted sequencing using the Ion Torrent Proton instrument revealed NF2 mutations in 45 cases (55%), LATS1 mutations in 2 cases (2%), and LATS2 mutations in 1 case (1%) of schwannoma. Methylation-specific polymerase chain reaction showed promoter methylation of LATS1 and LATS2 in 14 cases (17%) and 25 cases (30%), respectively. Overall, 62 cases (76%) had at least 1 alteration in the NF2, LATS1, and/or LATS2 genes. Immunohistochemistry revealed nuclear YAP expression in 18 of 42 cases of schwannoma (43%) and reduced cytoplasmic phosphorylated YAP expression in 15 of 49 cases of schwannoma (31%), all of which had at least 1 alteration in the NF2, LATS1, and/or LATS2 genes. These results suggest that an abnormal Hippo signaling pathway is involved in the pathogenesis of most sporadic schwannomas.
authors.affiliation: From the International Agency for Research on Cancer, Lyon, France (JEO, TO, KS, MF, GD, JM, FCK, HO); Institute of Neurology (Edinger Institute), Goethe-University Frankfurt, Frankfurt/Main, Germany (MM); and Department of Neurosurgery (BB) and Institute of Neuropathology (WP), University Hospital Munster, Munster, Germany.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Oh
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohta
authors.forename: Kaishi
authors.initials: K
authors.lastname: Satomi
authors.forename: Matthieu
authors.initials: M
authors.lastname: Foll
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Durand
authors.forename: James
authors.initials: J
authors.lastname: McKay
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brokinkel
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohgaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D016515:Genes, Neurofibromatosis 2 / Q000502:physiology*; D000090683:Hippo Signaling Pathway; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009442:Neurilemmoma / Q000235:genetics* / Q000378:metabolism*; D010750:Phosphoproteins / Q000502:physiology*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C092745:LATS1 protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases