| Literature DB >> 29730775 |
David Capper1,2,3,4,5, Nils W Engel6,7, Damian Stichel1, Matt Lechner8,9,10, Stefanie Glöss3,4,5, Simone Schmid3,4,5, Christian Koelsche1,2, Daniel Schrimpf1,2, Judith Niesen11,12, Annika K Wefers1,2, David T W Jones13,14, Martin Sill13,14, Oliver Weigert15, Keith L Ligon16, Adriana Olar17, Arend Koch3, Martin Forster9,10, Sebastian Moran18, Oscar M Tirado19, Miguel Sáinz-Jaspeado19, Jaume Mora20, Manel Esteller18,21,22, Javier Alonso23, Xavier Garcia Del Muro24, Werner Paulus25, Jörg Felsberg26,27, Guido Reifenberger26,27, Markus Glatzel28, Stephan Frank29, Camelia M Monoranu30, Valerie J Lund8,10, Andreas von Deimling1,2, Stefan Pfister13,14,31, Rolf Buslei32,33, Julika Ribbat-Idel34,35,36, Sven Perner34,35,36, Volker Gudziol37, Matthias Meinhardt38, Ulrich Schüller39,40,41,42.
Abstract
Olfactory 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.Entities:
Mesh：
Substances：
Year: 2018 PMID： 29730775 DOI： 10.1007/s00401-018-1854-7
Source DB: PubMed Journal: Acta Neuropathol ISSN： 0001-6322 Impact factor: 15.887