GENO-06A PAN-GLIOMA CHARACTERIZATION OF GENOMIC, EPIGENOMIC AND TRANSCRIPTOMIC ACTIVITIES REVEALS NOVEL RELATIONSHIPS BETWEEN HISTOLOGICAL SUBTYPES AND MOLECULAR SIGNATURES

Abstract

Although histopathologic classification of adult gliomas is well established, accurate diagnosis suffers from high intra- and inter-observer variability. In order to investigate the molecular underpinnings we performed an unbiased pan-glioma analysis of molecular features. We assembled the largest possible primary glioma dataset to date consisting of 1,122 TCGA samples of grades II-IV glioma that have been analyzed through mRNA sequencing and expression arrays (n = 1045), DNA methylation arrays (n = 932), exome sequencing (n = 833), DNA copy number arrays (n = 1084) and whole genome sequencing (WGS, n = 141). In addition to 30 known glioma drivers like IDH1, TP53, and EGFR, we identified 70 novel significantly mutated genes which were mutated at 0.5-3% frequency, including KRAS, NOTCH2 and ARID2. Novel copy number drivers included SETD2, ARID2, and GIGYF2. Analysis of WGS data identified enrichment for mutations in the promoter regions of TERT, CACNG6 and TRIM28 that were associated with a significant difference in mRNA expression, suggesting functional consequences. We used WGS based telomere length estimates and found that ATRX mutated samples showed significantly longer telomeres while TERT mutant samples showed shortened telomeres, independent of differences in age and IDH status. Unsupervised clustering of DNA methylation and gene expression resulted in six methylation subtypes and four expression subtypes. These clusters overlapped significantly disregarding tumor histopathology and could be divided into three macro groups separated by IDH mutations, TERT promoter mutations and 1p/19q co-deletion. Functional enrichments within-cluster revealed that grade IV tumors are primarily marked by a hyperproliferation signature with respect to grade II-III tumors which are characterized by increased activation of genes related to glial-neuronal functioning. These findings suggest that tumor grade reflects a point in time in the temporal evolution within individual glioma subtypes. Our analyses identified new drivers; suggest a novel association between telomere length and maintenance mechanisms and shed light on glioma evolution.