Olfactory neuroblastoma (ONB) is a rare, locally aggressive, malignant neoplasm originating in the olfactory epithelium in the nasal vault. The recurrence rate of ONB remains high and there are no specific treatment guidelines for recurrent/metastatic ONBs. This study retrospectively evaluated 23 ONB samples profiled at Caris Life Sciences (Phoenix, Arizona) using DNA sequencing (Sanger/NGS [Illumina], n = 15) and gene fusions (Archer FusionPlex, n = 6), whole genome RNA microarray (HumanHT-12 v4 beadChip, Illumina, n = 4), gene copy number assays (chromogenic and fluorescent in situ hybridization), and immunohistochemistry. Mutations were detected in 63% ONBs including TP53, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, and SMAD4 genes. Twenty-one genes were over-expressed and 19 genes under-expressed by microarray assay. Some of the upregulated genes included CD24, SCG2, and IGFBP-2. None of the cases harbored copy number variations of EGFR, HER2 and cMET genes, and no gene fusions were identified. Multiple protein biomarkers of potential response or resistance to classic chemotherapy drugs were identified, such as low ERCC1 [cisplatin sensitivity in 10/12], high TOPO1 [irinotecan sensitivity in 12/19], high TUBB3 [vincristine resistance in 13/14], and high MRP1 [multidrug resistance in 6/6 cases]. None of the cases (0/10) were positive for PD-L1 in tumor cells. Overexpression of pNTRK was observed in 67% (4/6) of the cases without underlying genetic alterations. Molecular alterations detected in our study (e.g., Wnt and cKIT/PDGFRA pathways) are potentially treatable using novel therapeutic approaches. Identified protein biomarkers of response or resistance to classic chemotherapy could be useful in optimizing existing chemotherapy treatment(s) in ONBs.

嗅神经母细胞瘤（ONB）是一种罕见的，局部侵袭性的，恶性肿瘤，起源于鼻腔的嗅上皮。ONB的复发率仍然很高，并且没有针对复发/转移性ONB的具体治疗指南。这项研究使用DNA测序（Sanger / NGS [Illumina]，n = 15）和基因融合蛋白（Archer FusionPlex，n = 6），全基因组RNA微阵列（HumanHT）回顾性评估了在Cari​​s Life Sciences（亚利桑那州凤凰城）进行分析的23个ONB样品-12 v4 beadChip，Illumina，n = 4），基因拷贝数测定（生色和荧光原位杂交）和免疫组化。在63％的ONB中检测到突变，包括TP53，CTNNB1，EGFR，APC，cKIT，cMET，PDGFRA，CDH1，FH和SMAD4基因。通过微阵列测定法，二十一个基因被过表达，而十九个基因被过表达。一些上调的基因包括CD24，SCG2和IGFBP-2。所有病例均未发现EGFR，HER2和cMET的拷贝数变异基因，没有发现基因融合体。鉴定出多种可能对经典化疗药物有反应或耐药的蛋白质标志物，例如低ERCC1 [顺铂敏感性为10/12]，高TOPO1 [伊立替康敏感性为12/19]，高TUBB3 [长春新碱抗性为13/14]，和高MRP1 [6/6例的多药耐药性]。肿瘤细胞中PD-L1均无阳性（0/10）。在没有潜在遗传改变的情况下，有67％（4/6）的病例观察到pNTRK的过度表达。在我们的研究中检测到的分子改变（例如Wnt和cKIT / PDGFRA途径）可以使用新型治疗方法来治疗。鉴定出的对经典化学疗法有反应或耐药的蛋白质生物标志物可能有助于优化ONB中现有的化学疗法。