Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas. Issue 10 (October 2015)

• Record Type: Journal Article
• Authors: Oh, Ji-Eun; Ohta, Takashi; Satomi, Kaishi; Foll, Matthieu; Durand, Geoffroy; McKay, James; Le Calvez-Kelm, Florence; Mittelbronn, Michel; Brokinkel, Benjamin; Paulus, Werner; Ohgaki, Hiroko
• Is Part Of: Journal of neuropathology and experimental neurology. Volume 74:Issue 10(2015:Oct.)
• Publication Date: 2015-10
• Subjects: Neurology -- Diseases -- Periodicals; Neurology -- Diseases -- Physiopathology -- Periodicals; 616.8047
• DOI: 10.1097/NEN.0000000000000238
• Languages: English
• ISSNs: 0022-3069

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Abstract</title> <p>Schwannomas are benign nerve sheath tumors composed of well-differentiated Schwann cells. Other than frequent <italic>NF2</italic> (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 <italic>NF2</italic>, <italic>LATS1</italic>, and <italic>LATS2</italic> genes, promoter methylation of <italic>LATS1</italic> and <italic>LATS2</italic>, and expression of YAP and phosphorylated YAP in 82 cases of sporadic schwannomas. Targeted sequencing using the Ion Torrent Proton instrument revealed <italic>NF2</italic> mutations in 45 cases (55%), <italic>LATS1</italic> mutations in 2 cases (2%), and <italic>LATS2</italic> mutations in 1 case (1%) of schwannoma. Methylation-specific polymerase chain reaction showed promoter methylation of <italic>LATS1</italic> and <italic>LATS2</italic> in 14 cases (17%) and 25 cases (30%), respectively. Overall, 62 cases (76%) had at least 1 alteration in the <italic>NF2</italic>, <italic>LATS1</italic>, and/or <italic>LATS2</italic> 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 <italic>NF2</italic>, <italic>LATS1</italic>, and/or <italic>LATS2</italic> genes. These results suggest that an abnormal Hippo signaling pathway is involved in the pathogenesis of most sporadic schwannomas.</p> </sec> </abstract>