P.085 Characterizing molecular alterations in glioma growth and progression

Abstract

Background: High grade gliomas (HGG) are incurable, aggressive brain malignances that carry poor prognoses. Significant scientific advances have uncovered many of the features of these diseases; however, it remains unclear how mutations and transcriptional changes drive glioma growth and progression. Methods: We used a Nestin-Cre mouse model in combination with an extrinsic chemical mutagen (N-ethyl-N-nitrosurea, ENU), to model HGG. We combined our mouse model with live animal in vivo magnetic resonance imaging to track tumor growth over time, and sample discrete lesions during premalignant, early stage tumor, and end stage tumor phases. Results: We show that the somatic mutations, copy number changes, and transcriptional profiles of tumors vary depending on the stage of growth, and that the Raf/Ras pathway is key for tumor growth with a recurring Braf mutation occurring in early stage lesions. Gene set enrichment analysis (GSEA) shows that end stage tumors have increased immunogenic/inflammatory activity, and increased signaling through Raf/Ras. Conclusions: The combination of genetic and nongenetic insults results in activating mutations in early lesions, which continue to be biologically active and underlie key differences between early and end stage tumors. Overall, this work sheds light on important differences between early and late stage tumors.