DNA methylation-based reclassification of olfactory neuroblastoma

• DOI: 10.1007/s00401-018-1854-7
• Publication Date: 2018-05-05T07:28:48Z
• Authors: David Capper; Nils W. Engel; Damian Stichel; Matt Lechner; Stefanie Glöss; Simone Schmid; Christian Koelsche; Daniel Schrimpf; Judith Niesen; Annika K. Wefers; David T. W. Jones; Martin Sill; Oliver Weigert; Keith L. Ligon; Adriana Olar; Arend Koch; Martin Forster; Sebastian Moran; Oscar M. Tirado; Miguel Sáinz-Jasp...; Jaume Mora; Manel Esteller; Javier Alonso; Xavier Garcia del...; Werner Paulus; Jörg Felsberg; Guido Reifenberger; Markus Glatzel; Stephan Frank; Camelia M. Monoranu; Valerie J. Lund; Andreas von Deimling; Stefan Pfister; Rolf Buslei; Julika Ribbat-Idel; Sven Perner; Volker Gudziol; Matthias Meinhardt; Ulrich Schüller
• Keywords: Adult; Aged, 80 and over; Male; 0301 basic medicine; Adolescent; DNA Methylation; Middle Aged; Isocitrate Dehydrogenase; 3. Good health; Diagnosis, Differential; Neuroblastoma; Olfaction Disorders; Young Adult; 03 medical and health sciences; Mutation; Biomarkers, Tumor; Humans; Female; Child; Transcriptome; Aged

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.