Characterization of the primitive neuroectodermal tumor genome using transposon-mediated insertional mutagenesis.

Abstract

Primitive neuroectodermal tumors (PNET) include medulloblastoma and supratentorial primitive neuroectodermal tumor subtypes that share histological features yet differ at the genomic level and in clinical outcome. Delineation of the genetic anomalies between PNET subtypes is a current challenge for establishing effective targeted therapeutic strategies against these aggressive tumors. Current efforts have demonstrated specific molecular pathways drive a minority of medulloblastoma and supratentorial PNET but the genetic basis of the majority of these tumors remains poorly understood and anecdotal. To better define the genetic causes of medulloblastoma and supratentorial PNET, we have developed a single Sleeping Beauty transposon insertional mutagenesis mouse model that recapitulates the morphological similarities and genetic heterogeneity of these tumor types capable of identifying genetic drivers important for PNETagenesis. This work has revealed biologically relevant candidate oncogenes and tumor suppressor genes for both medulloblastoma and supratentorial PNET in mice and humans. ARHGAP36 is a novel oncogene implicated in poorly understood MB molecular subgroups, and multiple RAS pathway effector genes were identified to be important for sPNET formation. Ultimately, these results present new understanding of the genetic basis for medulloblastoma and supratentorial PNET development and offer potential targets for therapeutic testing to improve patient clinical outcome.