Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas
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 y...
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| Veröffentlicht in: | Journal of neuropathology and experimental neurology 2015-10, Vol.74 (10), p.952-959 |
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| container_title | Journal of neuropathology and experimental neurology |
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| creator | Oh, Ji-Eun Ohta, Takashi Satomi, Kaishi Foll, Matthieu Durand, Geoffroy McKay, James Calvez-Kelm, Florence Le Mittelbronn, Michel Brokinkel, Benjamin Paulus, Werner Ohgaki, Hiroko |
| description | 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. |
| doi_str_mv | 10.1097/NEN.0000000000000238 |
| format | Article |
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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.</description><identifier>ISSN: 0022-3069</identifier><identifier>EISSN: 1554-6578</identifier><identifier>DOI: 10.1097/NEN.0000000000000238</identifier><identifier>PMID: 26360373</identifier><language>eng</language><publisher>England: American Association of Neuropathologists, Inc</publisher><subject>Adaptor Proteins, Signal Transducing - physiology ; Adult ; Aged ; DNA Mutational Analysis ; Female ; Genes, Neurofibromatosis 2 - physiology ; Hippo Signaling Pathway ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Neurilemmoma - genetics ; Neurilemmoma - metabolism ; Phosphoproteins - physiology ; Polymerase Chain Reaction ; Protein Serine-Threonine Kinases - physiology ; Signal Transduction - physiology ; Transcription Factors ; Tumor Suppressor Proteins - physiology ; YAP-Signaling Proteins</subject><ispartof>Journal of neuropathology and experimental neurology, 2015-10, Vol.74 (10), p.952-959</ispartof><rights>2015, by the American Association of Neuropathologists, Inc. 2015</rights><rights>2015 by American Association of Neuropathologists, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6298-9e2a8faf5c6e29268f08b90ac54d3aca5185231b7d651c5c3fa8709c112d71043</citedby><cites>FETCH-LOGICAL-c6298-9e2a8faf5c6e29268f08b90ac54d3aca5185231b7d651c5c3fa8709c112d71043</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26360373$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oh, Ji-Eun</creatorcontrib><creatorcontrib>Ohta, Takashi</creatorcontrib><creatorcontrib>Satomi, Kaishi</creatorcontrib><creatorcontrib>Foll, Matthieu</creatorcontrib><creatorcontrib>Durand, Geoffroy</creatorcontrib><creatorcontrib>McKay, James</creatorcontrib><creatorcontrib>Calvez-Kelm, Florence Le</creatorcontrib><creatorcontrib>Mittelbronn, Michel</creatorcontrib><creatorcontrib>Brokinkel, Benjamin</creatorcontrib><creatorcontrib>Paulus, Werner</creatorcontrib><creatorcontrib>Ohgaki, Hiroko</creatorcontrib><title>Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas</title><title>Journal of neuropathology and experimental neurology</title><addtitle>J Neuropathol Exp Neurol</addtitle><description>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.</description><subject>Adaptor Proteins, Signal Transducing - physiology</subject><subject>Adult</subject><subject>Aged</subject><subject>DNA Mutational Analysis</subject><subject>Female</subject><subject>Genes, Neurofibromatosis 2 - physiology</subject><subject>Hippo Signaling Pathway</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neurilemmoma - genetics</subject><subject>Neurilemmoma - metabolism</subject><subject>Phosphoproteins - physiology</subject><subject>Polymerase Chain Reaction</subject><subject>Protein Serine-Threonine Kinases - physiology</subject><subject>Signal Transduction - physiology</subject><subject>Transcription Factors</subject><subject>Tumor Suppressor Proteins - physiology</subject><subject>YAP-Signaling Proteins</subject><issn>0022-3069</issn><issn>1554-6578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkE1LwzAYx4Mobk6_gUiPXrrmpUmTg4cyNhXGHGwePIUsTWm1L7NpGfv2ZnaKeNEckofw-z_Pww-AawTHCIooWEwXY_jzYMJPwBBRGvqMRvwUDN0f9glkYgAurH11jIAiPAcDzAiDJCJDcBcXrWlUm9eV9fLKazPjLWY4mMfrFfq8cfASL72larOd2h-QlXZVVdWlspfgLFWFNVfHdwSeZ9P15MGfP90_TuK5rxkW3BcGK56qlGpmsMCMp5BvBFSahglRWlHEKSZoEyWMIk01SRWPoNAI4SRCMCQjcNv33Tb1e2dsK8vcalMUqjJ1ZyWKEKFYUAQdGvaobmprG5PKbZOXqtlLBOVBnHTi5G9xLnZznNBtSpN8h75MOYD3wK4-GLNvRbczjcyMKtrsr95BH6277f-2-QD90YOD</recordid><startdate>201510</startdate><enddate>201510</enddate><creator>Oh, Ji-Eun</creator><creator>Ohta, Takashi</creator><creator>Satomi, Kaishi</creator><creator>Foll, Matthieu</creator><creator>Durand, Geoffroy</creator><creator>McKay, James</creator><creator>Calvez-Kelm, Florence Le</creator><creator>Mittelbronn, Michel</creator><creator>Brokinkel, Benjamin</creator><creator>Paulus, Werner</creator><creator>Ohgaki, Hiroko</creator><general>American Association of Neuropathologists, Inc</general><general>by American Association of Neuropathologists, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201510</creationdate><title>Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas</title><author>Oh, Ji-Eun ; Ohta, Takashi ; Satomi, Kaishi ; Foll, Matthieu ; Durand, Geoffroy ; McKay, James ; Calvez-Kelm, Florence Le ; Mittelbronn, Michel ; Brokinkel, Benjamin ; Paulus, Werner ; Ohgaki, Hiroko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6298-9e2a8faf5c6e29268f08b90ac54d3aca5185231b7d651c5c3fa8709c112d71043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adaptor Proteins, Signal Transducing - physiology</topic><topic>Adult</topic><topic>Aged</topic><topic>DNA Mutational Analysis</topic><topic>Female</topic><topic>Genes, Neurofibromatosis 2 - physiology</topic><topic>Hippo Signaling Pathway</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neurilemmoma - genetics</topic><topic>Neurilemmoma - metabolism</topic><topic>Phosphoproteins - physiology</topic><topic>Polymerase Chain Reaction</topic><topic>Protein Serine-Threonine Kinases - physiology</topic><topic>Signal Transduction - physiology</topic><topic>Transcription Factors</topic><topic>Tumor Suppressor Proteins - physiology</topic><topic>YAP-Signaling Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oh, Ji-Eun</creatorcontrib><creatorcontrib>Ohta, Takashi</creatorcontrib><creatorcontrib>Satomi, Kaishi</creatorcontrib><creatorcontrib>Foll, Matthieu</creatorcontrib><creatorcontrib>Durand, Geoffroy</creatorcontrib><creatorcontrib>McKay, James</creatorcontrib><creatorcontrib>Calvez-Kelm, Florence Le</creatorcontrib><creatorcontrib>Mittelbronn, Michel</creatorcontrib><creatorcontrib>Brokinkel, Benjamin</creatorcontrib><creatorcontrib>Paulus, Werner</creatorcontrib><creatorcontrib>Ohgaki, Hiroko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of neuropathology and experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oh, Ji-Eun</au><au>Ohta, Takashi</au><au>Satomi, Kaishi</au><au>Foll, Matthieu</au><au>Durand, Geoffroy</au><au>McKay, James</au><au>Calvez-Kelm, Florence Le</au><au>Mittelbronn, Michel</au><au>Brokinkel, Benjamin</au><au>Paulus, Werner</au><au>Ohgaki, Hiroko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas</atitle><jtitle>Journal of neuropathology and experimental neurology</jtitle><addtitle>J Neuropathol Exp Neurol</addtitle><date>2015-10</date><risdate>2015</risdate><volume>74</volume><issue>10</issue><spage>952</spage><epage>959</epage><pages>952-959</pages><issn>0022-3069</issn><eissn>1554-6578</eissn><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.</abstract><cop>England</cop><pub>American Association of Neuropathologists, Inc</pub><pmid>26360373</pmid><doi>10.1097/NEN.0000000000000238</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Journals@Ovid Complete; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals |
| subjects | Adaptor Proteins, Signal Transducing - physiology Adult Aged DNA Mutational Analysis Female Genes, Neurofibromatosis 2 - physiology Hippo Signaling Pathway Humans Immunohistochemistry Male Middle Aged Neurilemmoma - genetics Neurilemmoma - metabolism Phosphoproteins - physiology Polymerase Chain Reaction Protein Serine-Threonine Kinases - physiology Signal Transduction - physiology Transcription Factors Tumor Suppressor Proteins - physiology YAP-Signaling Proteins |
| title | Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas |
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