GE-37 * INTEGRATED GENOMIC ANALYSIS OF LOW GRADE GLIOMA AND GLIOBLASTOMA REVEALS MOLECULAR STRATIFICATION BY IDH STATUS ACROSS GRADES AND HISTOLOGIES

Abstract

TCGA has performed comprehensive molecular characterization of glioblastoma (GBM) and diffuse low grade glioma (LGG), which suggested heterogeneity in clinical diagnosis: GBM with isocitrate dehydrogenase (IDH) gene mutations corresponded with a hypermethylator/G-CIMP phenotype and relatively favorable outcome, while IDH-wildtype LGG were associated with GBM-like genomic and methylation features and poor survival. By integrating the GBM and LGG datasets, the TCGA LGG-GBM working group aims to classify them in a clinically relevant manner and to shed light on potential targets for therapy. Unsupervised clustering of 289 LGG and 398 GBM using methylation profiles resulted into six major groups, mainly driven by IDH status and age. G-CIMP/IDH mutant GBM clustered with IDH mutant LGGs and IDHwt LGG grouped with IDHwt GBM. Some but not all LGG with 1p/19q co-deletion, a hallmark of oligodendroglioma, clustered separate from other LGGs and associated with less favorable outcome, suggesting clinical value of methylation based patient stratification. IDH-wildtype LGG and GBM clustered into a classical-mesenchymal class and a proneural-mesenchymal subtype, the latter with normal-like methylation features. Unsupervised transcriptome clustering of 282 LGGs and 152 GBMs was again driven by IDH status, followed by strong associations with mutations in TP53/ATRX. Supervised comparison of IDH wildtype LGG and GBM suggested upregulation of oxidative phosphorylation gene sets in GBM which may provide an intriguing possibility of pathogenetic differences between histologically different but genomically similar gliomas. We evaluated the distribution of genomic alterations in glioma disease pathways and found that G-CIMP GBM uniquely associated with abnormalities in the MYC pathway, revealing a possible explanation for the aggressive behavior of IDH-mutant GBM relative to IDH-mutant LGG. In this first of its kind study, we improve our understanding of gliomagenesis by identifying shared and subtype-unique disease pathways and provide new modalities towards integrated classification of diffuse low and high grade glioma.