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Identification of OTX1 and OTX2 As Two Possible Molecular Markers for Sinonasal Carcinomas and Olfactory Neuroblastomas
Published on: February 28, 2019
Comprehensive Molecular Profiling of Olfactory Neuroblastoma Identifies Potentially Targetable FGFR3 Amplifications
Lorena Lazo de la Vega1,2, Jonathan B McHugh1, Andi K Cani1,2
1Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
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 (n = 16), mxPCR-based RNA NGS of 108 target genes (n = 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 CCND1 [n = 4/18 (22%) tumors] and the targetable receptor tyrosine kinase FGFR3 [n = 5/18 (28%) tumors]. Targeted RNA NGS confirmed high expression of FGFR3 in ONB (at levels equivalent to bladder cancer), with the highest expression observed in FGFR3-amplified ONB cases. Importantly, our findings suggest that FGFR3 may be a therapeutic target in a subset of these aggressive tumors.Implications: ONBs harbor recurrent chromosomal copy-number changes, including FGFR3 amplification associated with overexpression. Hence, FGFR3 may represent a novel therapeutic target in these tumors. Mol Cancer Res; 15(11); 1551-7. ©2017 AACR.
Insights
Olfactory neuroblastomas (ONBs) show frequent copy-number alterations, including FGFR3 amplification. This suggests FGFR3 as a potential therapeutic target for these aggressive sinonasal cancers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Olfactory neuroblastomas (ONBs), or esthesioneuroblastomas, are rare sinonasal malignancies with aggressive behavior.
- Limited molecular data and lack of targeted therapies hinder effective treatment for ONBs.
Purpose of the Study:
- To identify oncogenic drivers and targetable pathways in olfactory neuroblastomas.
- To characterize the molecular landscape of ONBs through comprehensive genomic profiling.
Main Methods:
- DNA and RNA next-generation sequencing (NGS) were performed on 20 ONB samples.
- Targeted sequencing of over 400 cancer genes and >1,500 genes was utilized.
- Copy-number alterations and gene expression levels were analyzed.
Main Results:
- Somatic mutations were infrequent; however, copy-number alterations were detected in all tumors.
- Recurrent amplifications of CCND1 (22%) and FGFR3 (28%) were identified.
- FGFR3 amplification correlated with high FGFR3 expression, comparable to bladder cancer.
Conclusions:
- Olfactory neuroblastomas exhibit recurrent chromosomal copy-number changes, notably FGFR3 amplification.
- FGFR3 overexpression suggests its potential as a novel therapeutic target in a subset of ONBs.
