TMOD-28. UNDERSTANDING EGFRvIII GENOMIC BREAKPOINTS THROUGH CRISPR MODELING

Glioblastoma multiforme (GBM) is the most common and aggressive adult intracranial tumor accounting for 50% of diagnosed brain tumors every year. Genotypically, GBM’s express a variety of oncogenic mutations and amplifications including the epidermal growth factor receptor, EGFR. EGFR is the most frequently altered gene in GBM, being focally amplified in 40% of primary tumors. In a majority of these amplified EGFR cases, EGFRvIII is also present. The EGFRvIII mutant receptor is caused by recombination between loci in intron 1 and 7 leading to genomic deletion of exons 2-7, resulting in loss of part of the extracellular ligand-binding domain and constitutive signaling activity. Analysis of EGFR utilizing publically available data uncovered strong epigenetic regulatory signals in intron 1. Break points mapped from EGFRvIII deletions in patient samples and GBM cell lines within intron 1 reveal interesting patterns of deletion coordinates, with breakpoints often falling directly upstream of predicted enhancer regions as defined by the presence of strong ChIP-Seq peaks for histone marks H3K27Ac and H3K4me1. Together, these intron 1 enhancers have been identified as super-enhancers in U87 glioma cells. Chromatin interaction data suggests that these regions interact at long distance with the EGFR promoter. Putative enhancer regions in intron 1 are lost to varying degrees based upon the extent of deletion caused by the EGFRvIII mutation, the consequences of which are unkno...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MODELS Source Type: research