DNA methylation-based reclassification of olfactory neuroblastoma

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.

Pattern of loco‐regional relapses and treatment in pediatric esthesioneuroblastoma: The French very rare tumors group (Fracture) contribution

“…They showed that the basal‐like subgroup includes poorly differentiated tumors with a high expression of embryonic genes and a shorter survival for patients sharing some similarities with our cohort of pediatric ENBs (poor survival, dedifferentiated tumor, high Ki67). Interestingly, basal‐like ENBs harbor IDH2 mutations in one‐third of cases that might represent a therapeutic option …”

Epigenome-wide association study reveals CpG sites related to COG of neuroblastoma

“…Hypermethylation was found in aggressive tumors compared with low-grade ones [18], and the tumorigenic properties of NB was inhibited by reversing epigenetic changes in CpG island with demethylating agent [19]. Capper et al reported that DNA methylation patterns might be useful for the accurate classification of olfactory NB [20]. In this study, we analyzed the methylation data of NB in TARGET database, and found that the DNA methylation in the whole-genome that was associated with MKI, an indicator of NB histological classification [7], was significantly related to prognosis and survival.…”

Novel Biomarkers in Sinonasal Cancers: from Bench to Bedside

“…As such, despite morphological and immunophenotypical consistency, improved diagnostic methods are much needed. A recent study conducted by Capper et al (2018) showcased the reliability of methylation-based tumour profiling for more accurate diagnosis using a classifier system developed for brain tumours [ 10 ••, 11 ]. Furthermore, their study highlighted the likely prevalence of misdiagnosis in this malignancy and suggested that histology alone may frequently misdiagnose cases.…”