Comprehensive Molecular Profiling of Olfactory Neuroblastoma Identifies Potentially Targetable FGFR3 Amplifications
Autor: | Lorena Lazo de la Vega, Scott A. Tomlins, Arul M. Chinnaiyan, Jonathan B. McHugh, Daniel H. Hovelson, Chia Jen Liu, Frances M. Walocko, Paul W. Harms, Dan R. Robinson, Komal Kunder, Andi K. Cani |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Nonsynonymous substitution Genetics Cancer Research Olfactory Neuroblastoma Sequence analysis Biology Nose neoplasm Gene expression profiling 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis Gene duplication Cancer research Chromosome 20 Molecular Biology Gene |
Zdroj: | Molecular Cancer Research. 15:1551-1557 |
ISSN: | 1557-3125 1541-7786 |
Popis: | 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. |
Databáze: | OpenAIRE |
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