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000267352 037__ $$aDZNE-2024-00116
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000267352 1001_ $$aNeyazi, Sina$$b0
000267352 245__ $$aTranscriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation.
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000267352 520__ $$aEpendymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class 'spinal ependymoma' (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.
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000267352 650_7 $$2Other$$aClassification
000267352 650_7 $$2Other$$aDNA methylation
000267352 650_7 $$2Other$$aEpendymoma
000267352 650_7 $$2Other$$aNF2-related schwannomatosis
000267352 650_7 $$2Other$$aTranscriptomics
000267352 650_2 $$2MeSH$$aAdult
000267352 650_2 $$2MeSH$$aChild
000267352 650_2 $$2MeSH$$aHumans
000267352 650_2 $$2MeSH$$aTranscriptome
000267352 650_2 $$2MeSH$$aGene Expression Profiling
000267352 650_2 $$2MeSH$$aEpendymoma
000267352 650_2 $$2MeSH$$aSpinal Cord Neoplasms
000267352 650_2 $$2MeSH$$aMutation
000267352 650_2 $$2MeSH$$aEpigenesis, Genetic
000267352 7001_ $$aYamazawa, Erika$$b1
000267352 7001_ $$aHack, Karoline$$b2
000267352 7001_ $$aTanaka, Shota$$b3
000267352 7001_ $$aNagae, Genta$$b4
000267352 7001_ $$aKresbach, Catena$$b5
000267352 7001_ $$aUmeda, Takayoshi$$b6
000267352 7001_ $$aEckhardt, Alicia$$b7
000267352 7001_ $$aTatsuno, Kenji$$b8
000267352 7001_ $$aPohl, Lara$$b9
000267352 7001_ $$aHana, Taijun$$b10
000267352 7001_ $$aBockmayr, Michael$$b11
000267352 7001_ $$aKim, Phyo$$b12
000267352 7001_ $$0P:(DE-2719)2812547$$aDorostkar, Mario M$$b13
000267352 7001_ $$aTakami, Toshihiro$$b14
000267352 7001_ $$aObrecht, Denise$$b15
000267352 7001_ $$aTakai, Keisuke$$b16
000267352 7001_ $$aSuwala, Abigail K$$b17
000267352 7001_ $$aKomori, Takashi$$b18
000267352 7001_ $$aGodbole, Shweta$$b19
000267352 7001_ $$aWefers, Annika K$$b20
000267352 7001_ $$aOtani, Ryohei$$b21
000267352 7001_ $$aNeumann, Julia E$$b22
000267352 7001_ $$aHiguchi, Fumi$$b23
000267352 7001_ $$aSchweizer, Leonille$$b24
000267352 7001_ $$aNakanishi, Yuta$$b25
000267352 7001_ $$aMonoranu, Camelia-Maria$$b26
000267352 7001_ $$aTakami, Hirokazu$$b27
000267352 7001_ $$aEngertsberger, Lara$$b28
000267352 7001_ $$aYamada, Keisuke$$b29
000267352 7001_ $$aRuf, Viktoria$$b30
000267352 7001_ $$aNomura, Masashi$$b31
000267352 7001_ $$aMohme, Theresa$$b32
000267352 7001_ $$aMukasa, Akitake$$b33
000267352 7001_ $$0P:(DE-2719)2810441$$aHerms, Jochen$$b34
000267352 7001_ $$aTakayanagi, Shunsaku$$b35
000267352 7001_ $$aMynarek, Martin$$b36
000267352 7001_ $$aMatsuura, Reiko$$b37
000267352 7001_ $$aLamszus, Katrin$$b38
000267352 7001_ $$aIshii, Kazuhiko$$b39
000267352 7001_ $$aKluwe, Lan$$b40
000267352 7001_ $$aImai, Hideaki$$b41
000267352 7001_ $$avon Deimling, Andreas$$b42
000267352 7001_ $$aKoike, Tsukasa$$b43
000267352 7001_ $$aBenesch, Martin$$b44
000267352 7001_ $$aKushihara, Yoshihiro$$b45
000267352 7001_ $$aSnuderl, Matija$$b46
000267352 7001_ $$aNambu, Shohei$$b47
000267352 7001_ $$aFrank, Stephan$$b48
000267352 7001_ $$aOmura, Takaki$$b49
000267352 7001_ $$aHagel, Christian$$b50
000267352 7001_ $$aKugasawa, Kazuha$$b51
000267352 7001_ $$aMautner, Viktor F$$b52
000267352 7001_ $$aIchimura, Koichi$$b53
000267352 7001_ $$aRutkowski, Stefan$$b54
000267352 7001_ $$aAburatani, Hiroyuki$$b55
000267352 7001_ $$aSaito, Nobuhito$$b56
000267352 7001_ $$0P:(DE-2719)9000979$$aSchüller, Ulrich$$b57
000267352 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-023-02668-9$$gVol. 147, no. 1, p. 22$$n1$$p22$$tActa neuropathologica$$v147$$x0001-6322$$y2024
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