GENT-27. COMPREHENSIVE MOLECULAR CHARACTERIZATION OF N-ETHYL-N-NITROSOUREA INDUCED RAT GLIOMAS

Abstract

Gliomas affecting children and young adults are genetically distinct from those in older adults. Next-generation sequencing has revealed unique mutations, methylation patterns, and expression profiles, which now define age- and location-specific glioma subtypes. While most gliomas that arise in children and young adults have no known cause, epidemiologic studies have shown an association between maternal consumption during pregnancy of foods high in N-nitroso-compounds (NOCs) and the development of brain tumors in their children. Likewise, in utero exposure to NOCs is known to cause astrocytomas, oligodendrogliomas, and glioblastomas in young rats. Here we test the hypothesis that ENU-induced gliomas bear genomic and epigenetic alterations that resemble those found in the gliomas of children and young adults. The possibility that some gliomas are caused by exposures that are preventable and occur in utero is the clinical rationale for this study. Pregnant Sprague-Dawley rats were exposed to intravenous ENU and their offspring monitored by MRI for the development of gliomas. Animals were euthanized when they developed large gliomas (i.e., >5mm) or became symptomatic. Tumour tissues were harvested, cultured and analyzed histopathologically and immunohistochemically (IHC); RNA and DNA were also extracted from these tissues for sequencing and methylation studies. In our first cohort, all control pups were glioma-free and 11/11 pups exposed in utero developed MRI-detectable astrocytic gliomas. All tumours expressed ATRX, one expressed Olig2 and none were IDH R132H positive by IHC. Next-generation sequencing of tumor tissues is planned and three rat glioma cell lines have been established.