4484 - Classification of esthesioneuroblastoma (ENB) based on chromosome (chr) arm gain and loss (CNA) in the setting of a hypomutated genomic landscape

Background

ENB is a rare skull base tumor arising from the olfactory neuroepithelium with variable prognosis and no consensus guidelines for treatment. Previous genomic studies (Classe 2018, Capper 2018) have reported scant genomic alterations (GA) in advanced and metastatic ENB (mENB), including mutation of IDH2. Here, we explore the cytogenetic landscape of in 94 cases of mENB as assessed by NGS-based comprehensive genomic profiling (CGP).

Methods

Tumour specimens from 94 patients with mENB were assayed using hybrid capture-based CGP to delineate all classes of GA as point mutations, insertions deletions (indels), rearrangements and focal (<20 MB) amplifications or loss. Each chr was assessed for arm wide copy gain, loss of heterozygosity (LOH1, only one allele remaining) and copy neutral loss of heterozygosity (LOHx, 2+ identical alleles). % score by arm was utilized to generate two principal components and analysis was performed using distance based hierarchical clustering.

Results

mENB cases had 1 or fewer GA detected in 80% (75/94) of cases with a corresponding median tumor mutational burden of 1.5 mut/mb. TP53 was the most frequently altered gene in the cohort, while IDH2 mutations were found in only 2 cases (2.1%). Focal and homozygous deletions were identified in 11.7% (11/94) and 14.9% (14/94) of cases respectively. We then assessed chr arm gain and LOH1/X and identified a median of 11 events per case. Based on chr arm level changes, we identified 3 distinct subtypes of mENB: type IA (n = 53), defined by wide spread LOHx, type IB (n = 22), defined by wide spread LOH1, and type II (n = 19) generally lacking arm CNA. Type IB lacked chr5 or chr20 gain, which were both seen in 36% of type IA (p = 0.001). Patients with IA/B types were older than type II (mean 54.9 v 46.5 years, p = 0.015) and both IDH2 mutated cases segregated into type II.

Conclusions

Given the pauci-mutational genomic landscape of mENB, clustering by chr arm level changes identifies distinct classes of mENB, which were associated with biologic factors including age and IDH2 mutation. Further studies to correlate clinico-pathologic characteristics with the cytogenetic characteristics of these newly defined subtypes of mENB are needed.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Foundation Medicine Inc.

Funding

Foundation Medicine Inc.

Disclosure

R. Madison: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. D.C. Pavlick: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. S. Khan: Honoraria (self): Ariad; Honoraria (self): Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): EMD Serono; Honoraria (self): Genzyme; Honoraria (self): Guardant; Honoraria (self): Takeda; Honoraria (self): Oak Ridge Universities; Honoraria (self): Onyx Pharmaceuticals. J. Lee: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Leadership role, Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Officer / Board of Directors: Celcius Therapeutics. V.A. Miller: Leadership role, Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Scientific Advisory Board: Revolution Medicines. B.M. Alexander: Full / Part-time employment, Officer / Board of Directors: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Personal Fees: AbbVie; Advisory / Consultancy, Personal Fees: Schlesinger Associates; Advisory / Consultancy, Personal Fees: Bristol-Myers Squibb; Advisory / Consultancy, Personal Fees: Precision Health Economics; Research grant / Funding (self), grants outside submitted work: Puma Biotechnology; Research grant / Funding (self), grants outside submitted work: Celgene; Research grant / Funding (self), grants outside submitted work: Eli Lily. J. Chung: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. All other authors have declared no conflicts of interest. A.B. Schrock: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche.