LG-07 * MOSAIC GENETIC PROGRESSION MODELS OF LOW GRADE PEDIATRIC BRAIN TUMORS REVEAL UNIQUE FEATURES OF TUMOR EVOLUTION

Abstract

The past decade has seen the identification of several mutations associated with low grade pediatric glioma—notably those to the v-raf murine sarcoma viral oncogene homolog B1 (BRAF). Further, next generation sequencing has recently led to the discovery of a wide variety of recurrent somatic mutations associated with low grade gliomas as well as elucidating the landscape of genetic alterations in low and high grade glioma. We have employed a novel methodology, postnatal electroporation coupled with piggyBac transposition in order to rapidly interrogate the causality of these mutations in tumorigenesis. Introduction of somatic mutation to tumor cells lining the ventricular zone led to a characteristic hyperplasia denoted by dramatic overgrowth of mutant cells. However, the cells rapidly senesced. In the minority of cases, tumors transition into invasive high grade glioblastoma. Co-introduction of additional tumor suppressor targeting elements (shRNA against p16/p19, Trp53 shRNA) increased tumor grade. Here, we discuss findings from our functional investigations of these putative low grade driver mutations.