PMID- 28775129 OWN - NLM STAT- MEDLINE DCOM- 20180614 LR - 20180911 IS - 1557-3125 (Electronic) IS - 1541-7786 (Linking) VI - 15 IP - 11 DP - 2017 Nov TI - Comprehensive Molecular Profiling of Olfactory Neuroblastoma Identifies Potentially Targetable FGFR3 Amplifications. PG - 1551-1557 LID - 10.1158/1541-7786.MCR-17-0135 [doi] AB - 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. (c)2017 AACR. CI - (c)2017 American Association for Cancer Research. FAU - Lazo de la Vega, Lorena AU - Lazo de la Vega L AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan. FAU - McHugh, Jonathan B AU - McHugh JB AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. FAU - Cani, Andi K AU - Cani AK AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan. FAU - Kunder, Komal AU - Kunder K AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan. FAU - Walocko, Frances M AU - Walocko FM AD - University of Michigan Medical School, Ann Arbor, Michigan. FAU - Liu, Chia-Jen AU - Liu CJ AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan. FAU - Hovelson, Daniel H AU - Hovelson DH AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan. FAU - Robinson, Dan AU - Robinson D AD - Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan. FAU - Chinnaiyan, Arul M AU - Chinnaiyan AM AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan. AD - Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan. FAU - Tomlins, Scott A AU - Tomlins SA AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. paulharm@med.umich.edu tomlinss@umich.edu. AD - Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan. FAU - Harms, Paul W AU - Harms PW AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. paulharm@med.umich.edu tomlinss@umich.edu. AD - Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan. AD - Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170803 PL - United States TA - Mol Cancer Res JT - Molecular cancer research : MCR JID - 101150042 RN - 0 (CCND1 protein, human) RN - 136601-57-5 (Cyclin D1) RN - EC 2.7.10.1 (FGFR3 protein, human) RN - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 3) SB - IM MH - Adult MH - Aged MH - Cyclin D1/genetics MH - Esthesioneuroblastoma, Olfactory/*genetics/pathology MH - *Gene Amplification MH - Gene Expression Profiling/*methods MH - Gene Expression Regulation, Neoplastic MH - High-Throughput Nucleotide Sequencing/methods MH - Humans MH - Middle Aged MH - Nasal Cavity/*pathology MH - Neoplasm Grading MH - Nose Neoplasms/*genetics/pathology MH - Receptor, Fibroblast Growth Factor, Type 3/*genetics MH - Sequence Analysis, RNA/methods MH - Up-Regulation MH - Young Adult EDAT- 2017/08/05 06:00 MHDA- 2018/06/15 06:00 CRDT- 2017/08/05 06:00 PHST- 2017/03/13 00:00 [received] PHST- 2017/05/11 00:00 [revised] PHST- 2017/07/31 00:00 [accepted] PHST- 2017/08/05 06:00 [pubmed] PHST- 2018/06/15 06:00 [medline] PHST- 2017/08/05 06:00 [entrez] AID - 1541-7786.MCR-17-0135 [pii] AID - 10.1158/1541-7786.MCR-17-0135 [doi] PST - ppublish SO - Mol Cancer Res. 2017 Nov;15(11):1551-1557. doi: 10.1158/1541-7786.MCR-17-0135. Epub 2017 Aug 3.