Pediatric Brain Tumors

Primitive neuroectodermal tumors (PNET) of the brain include medulloblastoma (MB) and central nervous system primitive neuroectodermal tumor (CNS PNET) subtypes, which 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 that specific molecular pathways drive a subset of MB and CNS PNET, but the genetic basis for the deadliest forms of these tumors remains poorly understood and anecdotal. This is in part due to an overall lack of biologically relevant in vivo and in vitro model systems capable of direct comparison and identification of the genetic origins among PNET subtypes. Forward genetic, random mutagenesis in mice is an effective phenotype-driven method to model the genetic origins of human disease including cancer. We have applied this method to PNET by developing a single Sleeping Beauty transposon insertional mutagenesis mouse model that recapitulates the morphological similarities and genetic heterogeneity of MB and CNS PNET capable of identifying genetic drivers important for genesis of PNET. Importantly, this model has allowed new PNET phenotypes to be observed and is designed to reveal biologically relevant candidate oncogenes and tumor suppressor genes for MB and CNS PNET molecular subgroups in mice and humans. The ultimate goal of the approach we have taken is to uncover new understanding of the genetic basis for MB and CNS PNET development, how they are distinguished from each other, and offer potential targets for therapeutic testing to improve patient clinical outcome. Pediatric Brain Tumors Clinical and histological presentation of MB and CNS PNET. Malignant brain tumors are the most frequent solid cancer in children and consist of several different subtypes that pose distinct clinical challenges (1). High-grade malignancies comprise a significant portion of these intracranial lesions including gliomas (15-20%), MB (20%) (2), and CNS PNET (2%) (2). This review focuses on MB and CNS PNET, which are PNET subtypes defined by the World Health Organization (WHO) with useful guidelines for diagnosing their heterogeneous histological characteristics and malignancy grade (3). MB and CNS PNET are WHO grade IV embryonal tumors that occur most frequently in children and share several histopathological features including poorly differentiated small round cells of dense cellularity, high nucleus-to-cytoplasm ratio with frequently observed Homer-Wright rosettes (4). MB and CNS PNETs have also been observed in rare adult patients (5, 6). Fundamental differences include physiological location, with MB always occurring in the cerebellum, while CNS PNET arise in the cerebrum. CNS PNET patients also suffer an overall poorer prognosis (7, 8). Furthermore, MB can be subdivided into five histology subtypes with varying frequencies: classic (~70%), desmoplastic (7%), anaplastic (24%), large cell (10-22%), and MB with extensive nodularity (3%) (3, 9). Classic MB is the most common subtype and shares the most histological overlap with CNS PNET. Although rare, CNS PNET also include several histological 487 Correspondence to: David A. Largaespada, Ph.D., The Center For Genome Engineering and Masonic Cancer Center, University of Minnesota, 6-160 Jackson Hall, 321 Church Street South East, Minneapolis, MN 55455, U.S.A. Tel: +1 6126264979, Fax: +1 6126254648, e-mail: [email protected]