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000136668 1001_ $$0P:(DE-He78)51bf9ae9cb5771b30c483e5597ef606c$$aCapper, David$$b0$$eFirst author
000136668 245__ $$aDNA methylation-based reclassification of olfactory neuroblastoma.
000136668 260__ $$aBerlin$$bSpringer$$c2018
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000136668 520__ $$aOlfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.
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000136668 7001_ $$aEngel, Nils W$$b1
000136668 7001_ $$0P:(DE-He78)d20d08adc992abdb6ccffa1686f1ba17$$aStichel, Damian$$b2
000136668 7001_ $$aLechner, Matt$$b3
000136668 7001_ $$0P:(DE-HGF)0$$aGlöss, Stefanie$$b4
000136668 7001_ $$0P:(DE-HGF)0$$aSchmid, Simone$$b5
000136668 7001_ $$0P:(DE-HGF)0$$aKoelsche, Christian$$b6
000136668 7001_ $$0P:(DE-He78)e54a1e0999c1d8c95869ef9188b794cc$$aSchrimpf, Daniel$$b7
000136668 7001_ $$aNiesen, Judith$$b8
000136668 7001_ $$0P:(DE-HGF)0$$aWefers, Annika K$$b9
000136668 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b10
000136668 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b11
000136668 7001_ $$aWeigert, Oliver$$b12
000136668 7001_ $$aLigon, Keith L$$b13
000136668 7001_ $$aOlar, Adriana$$b14
000136668 7001_ $$aKoch, Arend$$b15
000136668 7001_ $$aForster, Martin$$b16
000136668 7001_ $$aMoran, Sebastian$$b17
000136668 7001_ $$aTirado, Oscar M$$b18
000136668 7001_ $$aSáinz-Jaspeado, Miguel$$b19
000136668 7001_ $$aMora, Jaume$$b20
000136668 7001_ $$aEsteller, Manel$$b21
000136668 7001_ $$aAlonso, Javier$$b22
000136668 7001_ $$aDel Muro, Xavier Garcia$$b23
000136668 7001_ $$aPaulus, Werner$$b24
000136668 7001_ $$0P:(DE-HGF)0$$aFelsberg, Jörg$$b25
000136668 7001_ $$0P:(DE-HGF)0$$aReifenberger, Guido$$b26
000136668 7001_ $$aGlatzel, Markus$$b27
000136668 7001_ $$aFrank, Stephan$$b28
000136668 7001_ $$aMonoranu, Camelia M$$b29
000136668 7001_ $$aLund, Valerie J$$b30
000136668 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b31
000136668 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b32
000136668 7001_ $$aBuslei, Rolf$$b33
000136668 7001_ $$aRibbat-Idel, Julika$$b34
000136668 7001_ $$aPerner, Sven$$b35
000136668 7001_ $$aGudziol, Volker$$b36
000136668 7001_ $$aMeinhardt, Matthias$$b37
000136668 7001_ $$00000-0002-8731-1121$$aSchüller, Ulrich$$b38
000136668 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-018-1854-7$$gVol. 136, no. 2, p. 255 - 271$$n2$$p255 - 271$$tActa neuropathologica$$v136$$x1432-0533$$y2018
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