{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:44:41Z","timestamp":1792788281920,"version":"4.5.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T00:00:00Z","timestamp":1603238400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T00:00:00Z","timestamp":1603238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Projekt DEAL"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Genomic studies of high-grade\/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade\/progressive meningiomas to date.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>850 high-grade\/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained\n                      <jats:italic>NF2<\/jats:italic>\n                      -mutant tumors (n\u2009=\u2009426, 50%), was associated with male sex (64.4%\u00a0%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0001) and often harbored additional mutations in\n                      <jats:italic>CDKN2A<\/jats:italic>\n                      \/\n                      <jats:italic>B<\/jats:italic>\n                      (24%), and the chromatin regulators\n                      <jats:italic>ARID1A<\/jats:italic>\n                      (9%), and\n                      <jats:italic>KDM6A<\/jats:italic>\n                      (6%). A second group (\n                      <jats:italic>NF2<\/jats:italic>\n                      -agnostic) featured\n                      <jats:italic>TERT<\/jats:italic>\n                      promoter (\n                      <jats:italic>TERT<\/jats:italic>\n                      p; n\u2009=\u200956) or\n                      <jats:italic>TP53<\/jats:italic>\n                      mutations (n\u2009=\u200925) and were either\n                      <jats:italic>NF2<\/jats:italic>\n                      -mutant or wild-type, and displayed no association with either sex (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.39). The remaining group generally lacked\n                      <jats:italic>NF2<\/jats:italic>\n                      mutations, and accounted for 40% of the cases\u2014with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators\n                      <jats:italic>BAP1<\/jats:italic>\n                      (n\u2009=\u200922) or\n                      <jats:italic>PBRM1<\/jats:italic>\n                      (n\u2009=\u200916). A second subgroup contained\n                      <jats:italic>AKT1<\/jats:italic>\n                      (n\u2009=\u200926),\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      (n\u2009=\u200914) and\n                      <jats:italic>SMO<\/jats:italic>\n                      (n\u2009=\u20097) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings indicate that the patterns of genomic alterations in high-grade\/progressive meningiomas commonly group into three different categories. The most common\n                      <jats:italic>NF2<\/jats:italic>\n                      -associated canonical group frequently harbored\n                      <jats:italic>CDKN2A<\/jats:italic>\n                      \/\n                      <jats:italic>B<\/jats:italic>\n                      alterations, which is potentially amenable to targeted therapies. An\n                      <jats:italic>NF2<\/jats:italic>\n                      -agnostic group harbored frequent\n                      <jats:italic>TERT<\/jats:italic>\n                      p and\n                      <jats:italic>TP53<\/jats:italic>\n                      mutations. The final subclass, distinct from the canonical\n                      <jats:italic>NF2<\/jats:italic>\n                      mutant associated pathway, was partly characterized by\n                      <jats:italic>BAP1<\/jats:italic>\n                      \/\n                      <jats:italic>PBRM1<\/jats:italic>\n                      alterations (rhabdoid\/papillary histology) or skull-base disease. Overall, these data increase our understanding of the pathobiology of high-grade\/progressive meningiomas and can guide the design of clinical trials.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IRB approval status<\/jats:title>\n                    <jats:p>Reviewed and approved by Western IRB; Protocol No. 20152817.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40478-020-01040-2","type":"journal-article","created":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T08:02:53Z","timestamp":1603267373000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["Distinct genomic subclasses of high-grade\/progressive meningiomas: NF2-associated, NF2-exclusive, and NF2-agnostic"],"prefix":"10.1186","volume":"8","author":[{"given":"Erik A.","family":"Williams","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Santagata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Wakimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh M.","family":"Shankar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"Fred G.","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radwa","family":"Sharaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhinav","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoebe","family":"Spear","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey S.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla K.","family":"Brastianos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Cahill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakti H.","family":"Ramkissoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2236-6719","authenticated-orcid":false,"given":"Tareq A.","family":"Juratli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,21]]},"reference":[{"key":"1040_CR1","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1093\/neuonc\/nov316","volume":"18","author":"M Abedalthagafi","year":"2016","unstructured":"Abedalthagafi M, Bi WL, Aizer AA, Merrill PH, Brewster R, Agarwalla PK, Listewnik ML, Dias-Santagata D, Thorner AR, Van Hummelen P et al (2016) Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. 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