{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T17:45:35Z","timestamp":1794332735864,"version":"4.9.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"8","funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8\u201316% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from preexisting benign plexiform neurofibromas (PNs) and atypical neurofibromas (ANFs). ANFs are distinct from both PN and MPNST, representing an intermediate step in malignant transformation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor\/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of 3 MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of 5 ANFs and 5 MPNSTs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a low number of mutations (median 1, range 0\u20135) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A\/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED and SUZ12 were frequently mutated, deleted, or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1\/2\/3, and CDK4\/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The PN-ANF transition is primarily driven by the deletion of CDKN2A\/B. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction and cell-cycle and pluripotency self-renewal genes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noz028","type":"journal-article","created":{"date-parts":[[2019,1,28]],"date-time":"2019-01-28T23:31:04Z","timestamp":1548718264000},"page":"981-992","source":"Crossref","is-referenced-by-count":121,"title":["Low mutation burden and frequent loss of CDKN2A\/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1\u2013associated atypical neurofibromas"],"prefix":"10.1093","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3893-3685","authenticated-orcid":false,"given":"Alexander","family":"Pemov","sequence":"first","affiliation":[{"name":"Clinical Genetics Branch, DCEG, NCI, National Institutes of Health (NIH), Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy F","family":"Hansen","sequence":"additional","affiliation":[{"name":"Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivasish","family":"Sindiri","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Patidar","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA"},{"name":"Molecular Characterization & Clinical Assay Development Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine S","family":"Higham","sequence":"additional","affiliation":[{"name":"Children\u2019s National Medical Center, Washington, DC, USA"},{"name":"Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Dombi","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markku M","family":"Miettinen","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, NCI, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Fetsch","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, NCI, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Brems","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Catholic University Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Settara C","family":"Chandrasekharappa","sequence":"additional","affiliation":[{"name":"Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine","family":"Jones","sequence":"additional","affiliation":[{"name":"Cancer Genomics Research Laboratory, DCEG, NIH, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Cancer Genomics Research Laboratory, DCEG, NIH, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun S","family":"Wei","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"National Intramural Sequencing Center (NISC) Comparative Sequencing Program","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"National Cancer Institute (NCI) Division of Cancer Epidemiology and Genetics (DCEG) Cancer Genomics Research Laboratory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C","family":"Mullikin","sequence":"additional","affiliation":[{"name":"Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Rockville, Maryland, USA"},{"name":"NISC, National Human Genome Research Institute, NIH, Rockville, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret R","family":"Wallace","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, UF Genetics Institute, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javed","family":"Khan","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Legius","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Catholic University Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte C","family":"Widemann","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas 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