GENE-04. PEDIATRIC MALIGNANT EPITHELIOID GLIONEURONAL TUMOR: PATHOLOGICAL, CLINICAL, AND MOLECULAR CHARACTERIZATION OF A RARE AND DEADLY MALIGNANCY

BACKGROUND: Malignant epithelioid glioneuronal tumor (MEGNT) is a rare high-grade brain tumor that exhibits both glial and neuronal differentiation and is not included in the current World Health Organization (WHO) classification. Limited case series describe a highly aggressive tumor with poor survival and have shed little light on MEGNT biology. AIM: The objective of our study was to molecularly characterize a cohort of MEGNTs in order to provide insight into tumor biology and identify potential therapeutic targets. METHODS: An integrated genomic strategy, including exome, transcriptome, and targeted mutation panel sequencing as well as copy number array analysis, was used to evaluate tumor samples obtained from 8 children with MEGNT. Clinical information was obtained by chart review. RESULTS: Outcomes were dismal for these patients despite aggressive surgery (gross total resection x 6) followed by involved field radiation therapy (XRT), with a median event-free survival of 6 months and 4 of 8 patients dead of disease. Frequent and potentially targetable genetic alterations were detected in the MAPK pathway in 4 of 8 cases (BRAF V600E x 3, NTRK2-BEND5) and in PI3K/MTOR pathway genes in 3 of 8 cases (TSC1 x 2, PTEN). Additional aberrations related to the MAPK pathway were identified in 4 patients, including high copy gains in MET and KIT and 2 novel fusions (SOS1-MAP4K3 and MAP3K11-GFAP) which were validated by targeted sequencing and require further functional characterization. Other alterations in known high-grade glioma genes were also detected, including homozygous CDKN2A/B loss (n=3), TP53 mutation (n=2), and amplification events involving MYCN, CDK6, MET, and KIT. CONCLUSION: MEGNT is an aggressive tumor with poor response to conventional therapies. The frequency of potentially-targetable molecular alterations identified in this study indicates an opportunity to test the use of novel targeted agents for children with these tumors.