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Multi-Omic Analysis Uncovers Two Subgroups of Rare Olfactory Cancer

NEW YORK (GenomeWeb) – In a multi-omic analysis, researchers have identified two subgroups of a rare olfactory cancer.

Esthesioneuroblastomas, also known as olfactory neuroblastomas, are rare tumors that affect about every four in 10 million people. These tumors develop at the base of the skull and grow into the nasal cavities.

A Sorbonne University-led team conducted an integrative analysis of primary esthesioneuroblastomas, and uncovered a basal subgroup and a neural subgroup. As they reported in Cell Reports today, the researchers found that these subtypes have distinct pathological, transcriptomic, and proteomic profiles. Specifically, they found that about a third of the basal subtype harbored an IDH2 variant reminiscent of gliomas, which might have treatment ramifications.

"Our study reveals insights into the molecular pathogenesis of [esthesioneuroblastoma] and provides classification information of potential therapeutic relevance," the Sorbonne's Gabriel Malouf and his colleagues wrote in their paper.

The researchers collected DNA and RNA from 59 different esthesioneuroblastoma samples for sequencing. These tumors harbored more than 600 mutations affecting 575 genes, but the researchers noted recurrent hotspot mutations at IDH2 R172 and TP53. IDH2 R172 hotspot mutations have also been reported in subsets of glioblastomas, leukemias, and osteosarcomas.

Clustering of these esthesioneuroblastomas based on their gene expression revealed two distinct subgroups, which the researchers dubbed basal and neural subtypes. More than 600 genes were upregulated in the basal subtype, as compared to the neural subtype, and these were enriched for involvement in cell division, cell proliferation, and neural tube closure. Meanwhile 1,220 genes were upregulated in the neural subtype, and were enriched for neuron modules like neurotransmitter secretion and nervous system development.

When the researchers further clustered esthesioneuroblastomas based on their protein-level expression and epigenetic profiles, those analyses also pointed to two subtypes that broadly matched the neural and basal subgroups.

About a third of the tumors belonging to the basal esthesioneuroblastoma subgroup harbored IDH2 R172 hotspot mutations, the researchers found. These hotspot mutations were only found in high-grade tumors with higher Ki67 proliferation indices. These tumors also had higher expression levels of cytokeratins, and lower expression of the neuroendocrine markers chromogranin A and synaptophysin, the team noted.

IDH2 mutant-esthesioneuroblastomas also exhibited a CpG island methylator phenotype (E-CIMP), similar to that of IDH2 mutant gliomas, the researchers reported. These tumors harbored pervasive DNA hypermethylation, particularly among the enhancers of axonal guidance genes.

This suggested to the investigators that the IDH2 mutation inhibits neural differential via genome-wide epigenetic reprogramming.

The researchers also investigated how the tumor microenvironment might influence esthesioneuroblastomas. They found that the mean count of CD4+ and CD8+ tumor-infiltrating lymphocytes was higher in the basal than in the neural esthesioneuroblastoma subtype, as well as the expression of cytotoxic cell markers. Despite this, the researchers noted that basal esthesioneuroblastomas were associated with worse prognosis.

Being able to stratify patients based on their tumor subtypes could also help guide their treatment, the researchers added.

"Beyond diagnostic implications, these findings have significant implications for therapy with IDH inhibitors, which have been recently approved to treat acute myeloid leukemia with a companion diagnostic along with the drug for IDH2 mutation detection," they wrote.