Comprehensive Molecular Profiling of Olfactory Neuroblastoma Identifies Potentially Targetable FGFR3 Amplifications

Abstract

Olfactory neuroblastomas (ONBs), also known as esthesioneuroblastomas, are malignant round-cell tumors that represent up to 5% of sinonasal malignancies. Despite their aggressive course, molecular studies of ONBs have been limited, and targeted therapies are lacking. To identify potential oncogenic drivers and targetable pathways in ONBs, we characterized 20 ONBs, including archived ONBs profiled by targeted, multiplexed PCR (mxPCR)-based DNA next-generation sequencing (NGS) of the coding sequence of over 400 cancer-relevant genes ( = 16), mxPCR-based RNA NGS of 108 target genes ( = 15), and 2 ONBs profiled by comprehensive hybrid-capture-based clinical grade NGS of >1,500 genes. Somatic mutations were infrequent in our cohort, with 7 prioritized nonsynonymous mutations in 5 of 18 (28%) ONBs, and no genes were recurrently mutated. We detected arm/chromosome-level copy-number alterations in all tumors, most frequently gains involving all or part of chromosome 20, chromosome 5, and chromosome 11. Recurrent focal amplifications, often but not exclusively in the context of arm-level gains, included [ = 4/18 (22%) tumors] and the targetable receptor tyrosine kinase [ = 5/18 (28%) tumors]. Targeted RNA NGS confirmed high expression of in ONB (at levels equivalent to bladder cancer), with the highest expression observed in-amplified ONB cases. Importantly, our findings suggest that FGFR3 may be a therapeutic target in a subset of these aggressive tumors. ONBs harbor recurrent chromosomal copy-number changes, including amplification associated with overexpression. Hence, FGFR3 may represent a novel therapeutic target in these tumors..

Comprehensive molecular profiling of advanced/metastatic olfactory neuroblastomas

“…These results indicate a limited therapeutic benefit of EGFR inhibitors in ONB patients. Mutations in TP53 gene were also detected in other studies that performed DNA sequence analysis in ONB samples [ 13 – 17 ]. Due to the disease progression in those patients, a role of TP53 mutation as an unfavorable prognostic and predictive factor in ONB has been suggested [ 18 ].…”

“…Currently only a few studies have investigated genomic landscape of ONBs, using different sequencing techniques [ 13 – 17 ]. Furthermore, in three of these studies the potential of targeted therapy with specific drugs was explored.…”

Evaluating the prognostic potential of the Ki67 proliferation index and tumour‐infiltrating lymphocytes in olfactory neuroblastoma

“…reported different mutational profiles in low‐grade and high‐grade ONBs, with no recurrent mutations in low‐grade ONBs, and IDH2 and TP53 mutations in higher‐grade ONBs. TP53 mutations have also been reported by others in high grade ONBs . It is possible that high‐grade tumours have a higher mutational load than low‐grade tumours, or have mutations that are more immunogenic.…”

“…This might be due to the stronger immunogenic profile of high‐grade tumours. The mutational landscape of ONBs is still poorly known . Classe et al .…”

Utility of adjuvant chemotherapy in patients receiving surgery and adjuvant radiotherapy for primary treatment of esthesioneuroblastoma

“…This is evidenced by recent case reports showing durable responses in patients treated with tyrosine kinase inhibitors after identifying particular mutations, such as, EGFR (cetuximab), RET (sunitinib), PDGFRB (sunitinib), and KIT (imatinib), and also in a patient treated with anti‐vascular endothelial derived growth factor (VEGF) therapy (bevacizumab) . What is more, recent studies have revealed targetable genomic lesions in canonical signaling pathways in primary ENB samples, including FGFR , PIK3CA , PTEN , and NF1 , several members of the Wnt/β‐catenin pathway, as well as mutations in critical regulators of the cell cycle, such as CDKN2C and CDKN2A . All of these somatic alterations could offer therapeutic opportunities in ENB.…”