GENE-12. ANAPLASTIC NEUROEPITHELIAL TUMOR WITH CONDENSED NUCLEI (ANTCON): A NOVEL BRAIN TUMOR ENTITY WITH RECURRENT NTRK FUSION Free

Brain tumors presenting with histological and molecular features not matching any established category in the WHO classification are challenging for diagnosticians and clinicians. Albeit rare, these cases can belong to distinct, as of yet not recognized entities. Based on unsupervised clustering of DNA methylation data from >30,000 tumors, we identified a group of tumors forming a cluster separate from all established entities. Histological reports revealed varying diagnoses and WHO grading. DNA and/or RNA sequencing of nine cases revealed NTRK fusions in five samples and fusions involving EGFR, FGFR1 and MET in single cases. Homozygous deletion at 9p21 encompassing CDKN2A/B were detected in 4/9 patients (44%). No other recurrent, focal copy number aberrations were observed. Considering cellular differentiation, histological features of anaplasia with high proliferative activity and the endothelial proliferation, the tumor entity was termed anaplastic neuroepithelial tumor with condensed nuclei (ANTCoN). The clinical findings provisionally support its classification as WHO grade III. The high frequency of NTRK fusions opens opportunities for targeted therapy. As a pre-clinical platform, a representative mouse model of an NTRK2-fused tumor with deletion of CDKN2A/B was generated using in utero electroporation in CD1 immunocompetent mice. A combination of the fusion plus loss-of-function of either p53 or cdkn2a resulted in tumors with a penetrance of 96% and mean latencies of 42.6 and 74.5 days, respectively. Histology of the murine tumors resembled human ANTCoN. This model will allow comparing the efficacy of Trk inhibitors in vivo to accelerate pre-clinical testing towards drug approval. In summary, the identification of this novel entity underlines the concept of the current WHO classification for brain tumors, that virtually all cases can be clearly categorized based on combined histological and molecular profiling. The detection of promising therapeutic targets in such groups, as in ANTCoN, can also provide significant opportunities for treatment.