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..

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<p>Figure S1. (A) Overexpression of p53 in olfactory neuroblastoma tumor harboring an inactivating TP53 mutation. (B) Representative example of p53 expression in olfactory neuroblastoma tumor lacking TP53 mutation. Immunohistochemistry, 400x magnification. figure S2. (A) Nuclear localization of beta catenin in olfactory neuroblastoma tumor harboring an activating CTNNB1 mutation. (B) Representative example of membranous beta catenin expression in olfactory neuroblastoma tumor lacking CTNNB1 mutation. Immunohistochemistry, 400x magnification. Table S1: Immunohistochemistry protocols Table S2: Clinicopathologic features of olfactory neuroblastoma cohort Table S3: DNA sequencing statistics for profiled olfactory neuroblastoma samples Table S4: Prioritized somatic nonsynonymous mutations in olfactory neuroblastoma cases identified by next generation sequencing Table S5: FGFR3 copy number in olfactory neuroblastomas by next generation sequencing Table S6. Targeted multiplexed PCR based RNA sequencing statistics for ONB samples</p>

<p>Figure S1. (A) Overexpression of p53 in olfactory neuroblastoma tumor harboring an inactivating TP53 mutation. (B) Representative example of p53 expression in olfactory neuroblastoma tumor lacking TP53 mutation. Immunohistochemistry, 400x magnification. figure S2. (A) Nuclear localization of beta catenin in olfactory neuroblastoma tumor harboring an activating CTNNB1 mutation. (B) Representative example of membranous beta catenin expression in olfactory neuroblastoma tumor lacking CTNNB1 mutation. Immunohistochemistry, 400x magnification. Table S1: Immunohistochemistry protocols Table S2: Clinicopathologic features of olfactory neuroblastoma cohort Table S3: DNA sequencing statistics for profiled olfactory neuroblastoma samples Table S4: Prioritized somatic nonsynonymous mutations in olfactory neuroblastoma cases identified by next generation sequencing Table S5: FGFR3 copy number in olfactory neuroblastomas by next generation sequencing Table S6. Targeted multiplexed PCR based RNA sequencing statistics for ONB samples</p>