{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:38:31Z","timestamp":1790033911395,"version":"4.0.1"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:00:00Z","timestamp":1677715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Mildred Scheel Cancer Career Center"},{"name":"F\u00f6rdergemeinschaft Kinderkrebszentrum Hamburg"},{"DOI":"10.13039\/501100017655","name":"Friedberg Charitable Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017655","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nothing is Forever"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A\/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Unsupervised class discovery and t-SNE analysis indicated that 36\/40 ANF cluster with benign peripheral nerve sheath tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had a frequent heterozygous or homozygous loss of CDKN2A\/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noad053","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T18:17:00Z","timestamp":1677521820000},"page":"1644-1655","source":"Crossref","is-referenced-by-count":21,"title":["Atypical neurofibromas reveal distinct epigenetic features with proximity to benign peripheral nerve sheath tumor entities"],"prefix":"10.1093","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6004-7332","authenticated-orcid":false,"given":"Catena","family":"Kresbach","sequence":"first","affiliation":[{"name":"Department of Diagnostics, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf , Germany"},{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"},{"name":"Research Institute Children\u2019s Cancer Center , Hamburg , Germany"},{"name":"Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg- Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9769-7080","authenticated-orcid":false,"given":"Matthias","family":"Dottermusch","sequence":"additional","affiliation":[{"name":"Department of Diagnostics, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Eckhardt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"},{"name":"Research Institute Children\u2019s Cancer Center , Hamburg , Germany"},{"name":"Lab of Radiobiology & Experimental Radiation Oncology, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3032-2321","authenticated-orcid":false,"given":"Inka","family":"Ristow","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petros","family":"Paplomatas","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"},{"name":"Research Institute Children\u2019s Cancer Center , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Altendorf","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"},{"name":"Research Institute Children\u2019s Cancer Center , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9394-8519","authenticated-orcid":false,"given":"Annika K","family":"Wefers","sequence":"additional","affiliation":[{"name":"Department of Diagnostics, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf , Germany"},{"name":"Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg- Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9249-4292","authenticated-orcid":false,"given":"Michael","family":"Bockmayr","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"},{"name":"Research Institute Children\u2019s Cancer Center , Hamburg , Germany"},{"name":"Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg- Eppendorf , Hamburg , Germany"},{"name":"Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Institute of Pathology , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarra","family":"Belakhoua","sequence":"additional","affiliation":[{"name":"Department of Pathology, NYU Langone Health and School of Medicine , New York, New York , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivy","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Pathology, NYU Langone Health and School of Medicine , New York, New York , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Pohl","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"},{"name":"Research Institute Children\u2019s Cancer Center , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9861-2325","authenticated-orcid":false,"given":"Sina","family":"Neyazi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"},{"name":"Research Institute Children\u2019s Cancer Center , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Bode","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"},{"name":"Research Institute Children\u2019s Cancer Center , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3596-5932","authenticated-orcid":false,"given":"Said","family":"Farschtschi","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2491-1346","authenticated-orcid":false,"given":"Lennart","family":"Well","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7747-9636","authenticated-orcid":false,"given":"Reinhard E","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2269-5192","authenticated-orcid":false,"given":"David","family":"Reuss","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, University of Heidelberg , Heidelberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0752-0917","authenticated-orcid":false,"given":"Matija","family":"Snuderl","sequence":"additional","affiliation":[{"name":"Department of Pathology, NYU Langone Health and School of Medicine , New York, New York , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0518-0824","authenticated-orcid":false,"given":"Christian","family":"Hagel","sequence":"additional","affiliation":[{"name":"Department of Diagnostics, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1953-5182","authenticated-orcid":false,"given":"Victor-Felix","family":"Mautner","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8731-1121","authenticated-orcid":false,"given":"Ulrich","family":"Sch\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Diagnostics, Institute of Neuropathology, University Medical Center Hamburg-Eppendorf , Germany"},{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany"},{"name":"Research Institute Children\u2019s Cancer Center , Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,2]]},"reference":[{"issue":"1","key":"2023090516413138500_CIT0001","first-page":"1","article-title":"The MEK inhibitor selumetinib reduces spinal neurofibroma burden in patients with NF1 and plexiform neurofibromas","volume":"2","author":"Jackson","year":"2020","journal-title":"Neurooncol Adv."},{"issue":"11","key":"2023090516413138500_CIT0002","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1093\/neuonc\/noac146","article-title":"Management of neurofibromatosis type 1-associated plexiform neurofibromas","volume":"24","author":"Fisher","year":"2022","journal-title":"Neuro Oncol."},{"issue":"12","key":"2023090516413138500_CIT0003","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1038\/s41416-018-0073-2","article-title":"Cutaneous neurofibromas in the genomics era: current understanding and open questions","volume":"118","author":"Allaway","year":"2018","journal-title":"Br J Cancer."},{"issue":"2","key":"2023090516413138500_CIT0004","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.stemcr.2019.01.001","article-title":"Reprogramming Captures the Genetic and Tumorigenic Properties of Neurofibromatosis Type 1 Plexiform Neurofibromas","volume":"12","author":"Carri\u00f3","year":"2019","journal-title":"Stem Cell Rep."},{"issue":"12","key":"2023090516413138500_CIT0005","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1002\/gcc.20921","article-title":"Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors","volume":"50","author":"Beert","year":"2011","journal-title":"Genes Chromosomes Cancer."},{"issue":"11","key":"2023090516413138500_CIT0006","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1038\/ng.3116","article-title":"Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors","volume":"46","author":"Zhang","year":"2014","journal-title":"Nat Genet."},{"issue":"11","key":"2023090516413138500_CIT0007","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/ng.3095","article-title":"PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors","volume":"46","author":"Lee","year":"2014","journal-title":"Nat Genet."},{"issue":"6","key":"2023090516413138500_CIT0008","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.2214\/AJR.09.2724","article-title":"MRI features in the differentiation of malignant peripheral nerve sheath tumors and neurofibromas","volume":"194","author":"Wasa","year":"2010","journal-title":"AJR Am J Roentgenol."},{"issue":"5","key":"2023090516413138500_CIT0009","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s00259-012-2314-6","article-title":"Evaluation of intratumoural heterogeneity on 18F-FDG PET\/CT for characterization of peripheral nerve sheath tumours in neurofibromatosis type 1","volume":"40","author":"Salamon","year":"2013","journal-title":"Eur J Nucl Med Mol Imaging."},{"issue":"4","key":"2023090516413138500_CIT0010","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1093\/neuonc\/noaa280","article-title":"A Bayesian approach for diagnostic accuracy of malignant peripheral nerve sheath tumors: a systematic review and meta-analysis","volume":"23","author":"Martin","year":"2021","journal-title":"Neuro Oncol."},{"issue":"11","key":"2023090516413138500_CIT0011","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.humpath.2017.05.010","article-title":"Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview","volume":"67","author":"Miettinen","year":"2017","journal-title":"Hum Pathol."},{"key":"2023090516413138500_CIT0012","article-title":"Central nervous system tumours","volume-title":"World Health Organization Classification of Tumours","author":"Louis","year":"2021","edition":"5"},{"issue":"16","key":"2023090516413138500_CIT0013","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1093\/hmg\/ddz095","article-title":"Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation","volume":"28","author":"Rhodes","year":"2019","journal-title":"Hum Mol Genet."},{"issue":"1","key":"2023090516413138500_CIT0014","doi-asserted-by":"crossref","first-page":"14992","DOI":"10.1038\/s41598-017-15183-1","article-title":"The genomic landscape of malignant peripheral nerve sheath tumors: diverse drivers of Ras pathway activation","volume":"7","author":"Brohl","year":"2017","journal-title":"Sci Rep."},{"issue":"7697","key":"2023090516413138500_CIT0015","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature26000","article-title":"DNA methylation-based classification of central nervous system tumours","volume":"555","author":"Capper","year":"2018","journal-title":"Nature."},{"issue":"1","key":"2023090516413138500_CIT0016","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/s41467-020-20603-4","article-title":"Sarcoma classification by DNA methylation profiling","volume":"12","author":"Koelsche","year":"2021","journal-title":"Nat Commun."},{"issue":"1","key":"2023090516413138500_CIT0017","doi-asserted-by":"crossref","first-page":"1932365","DOI":"10.1080\/2162402X.2021.1932365","article-title":"DIMEimmune: Robust estimation of infiltrating lymphocytes in CNS tumors from DNA methylation profiles","volume":"10","author":"Safaei","year":"2021","journal-title":"Oncoimmunology."},{"issue":"5","key":"2023090516413138500_CIT0018","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1097\/PAP.0000000000000162","article-title":"Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immunooncology biomarkers working group: part 1: assessing the host immune response, tils in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research","volume":"24","author":"Hendry","year":"2017","journal-title":"Adv Anat Pathol."},{"issue":"1","key":"2023090516413138500_CIT0019","doi-asserted-by":"crossref","first-page":"1779990","DOI":"10.1080\/2162402X.2020.1779990","article-title":"Inflammation and lymphocyte infiltration are associated with shorter survival in patients with high-grade glioma","volume":"9","author":"Marinari","year":"2020","journal-title":"Oncoimmunology."},{"issue":"Suppl 1","key":"2023090516413138500_CIT0020","first-page":"i23","article-title":"After Nf1 loss in Schwann cells, inflammation drives neurofibroma formation","volume":"2","author":"Fletcher","year":"2020","journal-title":"Neurooncol Adv."},{"issue":"47","key":"2023090516413138500_CIT0021","doi-asserted-by":"crossref","first-page":"82037","DOI":"10.18632\/oncotarget.18301","article-title":"Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy","volume":"8","author":"Haworth","year":"2017","journal-title":"Oncotarget."},{"issue":"8","key":"2023090516413138500_CIT0022","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1002\/humu.23552","article-title":"Analysis of intratumor heterogeneity in Neurofibromatosis type 1 plexiform neurofibromas and neurofibromas with atypical features: Correlating histological and genomic findings","volume":"39","author":"Carri\u00f3","year":"2018","journal-title":"Hum Mutat."},{"issue":"6","key":"2023090516413138500_CIT0023","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1007\/s00401-016-1540-6","article-title":"Methylation-based classification of benign and malignant peripheral nerve sheath tumors","volume":"131","author":"R\u00f6hrich","year":"2016","journal-title":"Acta Neuropathol."},{"issue":"2","key":"2023090516413138500_CIT0024","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/bpa.12228","article-title":"Melanotic tumors of the nervous system are characterized by distinct mutational, chromosomal and epigenomic profiles","volume":"25","author":"Koelsche","year":"2015","journal-title":"Brain Pathol."},{"issue":"3","key":"2023090516413138500_CIT0025","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.neuroimage.2006.01.015","article-title":"User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability","volume":"31","author":"Yushkevich","year":"2006","journal-title":"Neuroimage."},{"issue":"2","key":"2023090516413138500_CIT0026","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s00401-018-1879-y","article-title":"Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience","volume":"136","author":"Capper","year":"2018","journal-title":"Acta Neuropathol."},{"issue":"7","key":"2023090516413138500_CIT0027","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1111\/nan.12330","article-title":"The putative oncogene CPI-17 is up-regulated in schwannoma","volume":"42","author":"Hagel","year":"2016","journal-title":"Neuropathol Appl Neurobiol."}],"container-title":["Neuro-Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/advance-article-pdf\/doi\/10.1093\/neuonc\/noad053\/49803427\/noad053.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/25\/9\/1644\/51360681\/noad053.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/25\/9\/1644\/51360681\/noad053.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T12:42:58Z","timestamp":1693917778000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article\/25\/9\/1644\/7067960"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,2]]},"references-count":27,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,3,2]]},"published-print":{"date-parts":[[2023,9,5]]}},"URL":"https:\/\/doi.org\/10.1093\/neuonc\/noad053","relation":{},"ISSN":["1522-8517","1523-5866"],"issn-type":[{"value":"1522-8517","type":"print"},{"value":"1523-5866","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,9,1]]},"published":{"date-parts":[[2023,3,2]]}}}