Genetic Alterations in Olfactory Neuroblastoma: Insights from the AACR Genie Database

Purpose: Olfactory neuroblastoma (esthesioneuroblastoma, ONB) is a rare malignant neoplasm arising from olfactory neuroepithelium. ONB is characterized by its neural crest origin and distinctive histopathological features, but there is limited information on their somatic mutational landscape. Current treatment options include surgery, radiotherapy, and induction chemotherapy, but there are no standard treatments for advanced or recurrent disease. Currently, there are clinical trials for biologic therapies for ONB, such as apatinib and sunitinib, small-molecule tyrosine kinase inhibitor (TKI) that targets VEGFR-2. In this study, we aim to identify common mutations and genetic alterations to understand the molecular basis of ONB in support of the development of targeted therapies.

Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database was accessed from cBioPortal (v16.1-public) on July 22, 2024, to identify all patients with ONB. The most common gene mutations, gene correlations, and mutual exclusivities were assessed using a two-sided T-test and nonparametric tests, with Benjamini-Hochberg False Discovery Rate (FDR) correction.

Results: Of the 634 patients with embryonal tumors, 37 (5.8%) had olfactory neuroblastoma. In this cohort, 23 (62.2%) patients were male and 14 (37.8%) were female. The majority (n = 26; 70.3%) of patients were White, and there was the same number (n = 3; 8.1%) of Asian and Black patients. Five (13.5%) patients were pediatric and 32 (86.5%) were adult. The top mutations in the cohort were: TP53 (n = 6; 16.2%), FRK (n = 6; 16.2%), NOTCH3 (n = 3; 8.1%), SMARCA4 (n = 3; 8.1%), RET (n = 3; 8.1%), and CTCF (n = 3; 8.1%). In terms of specific mutation types, NOTCH3, SMARCA4, RET, and CTCF were all missense mutations, with no specific pattern of point mutations. The majority of mutations on TP53 were also missense mutations (n = 4; 66.7%). For gene FRK, the majority of mutations were in-frame deletions (n = 4; 66.7%), and the most common protein affected was R181, resulting in its deletion or alteration (n = 4; 66.7%). Of the top nine most commonly mutated genes, there were no other statistically significant co-occurrences or mutual exclusivities.

Conclusion: TP53 and FRK mutations were the most prevalent in olfactory neuroblastoma, each accounting for 16.2% of cases in this cohort. Notably, FRK mutations predominantly consist of in-frame deletions or alterations affecting the R181 protein. Additionally, the presence of mainly missense-type mutations in NOTCH3, SMARCA4, RET, and CTCF may contribute to the current understanding of the molecular pathogenesis of ONB and guide drug development. For example, VEGF inhibitors in clinical trials decrease the molecular products necessary for cellular proliferation through RET-mediated PI3K-AKT signaling. Additionally, since FRK is a tyrosine kinase involved in cell signaling and regulation, the tyrosine kinase inhibitors currently in clinical trials may be promising for ONB with FRK mutations. Understanding these mutational landscapes may accelerate the development of novel ONB-targeted therapy.

Publication History

Article published online:
07 February 2025