EPIG-14EPIGENOMIC (DNA METHYLATION AND EXPRESSION) SIGNATURES DEFINE SUBSETS OF BOTH IDHmut AND IDHwt GLIOMA WITH DISTINCT CLINICAL OUTCOMES

TCGA Glioma working group recently performed comprehensive characterization studies of both low grade glioma (LGG) and primary glioblastoma (GBM), which independently identified strong heterogeneity in clinical diagnosis using genome-wide aberrant DNA methylation (Brennan et al Cell 2013 and TCGA NEJM 2015). By integrating the GBM and LGG DNA methylation data, we aimed to investigate the discordance among the clinical subtypes. We performed unsupervised clustering of DNA methylation profiles of 932 gliomas (516 LGG and 416 GBM) and identified 6 robust groups (LGm1-6). LGm1-3 can be characterized as enriched for IDHmut (451/454, 99%) and was mostly LGG (421/454, 92.7%). In contrast, LGm4-6 was IDHwt (477/478, 99.8%) and was predominantly GBM (383/478, 80%). LGm1-3 showed distinct hypermethylation across the whole genome compared to LGm4-6 clusters, however there were distinct methylation subtypes within the LGm1-3 that stratified the IDHmut into two subgroups. Interestingly, the previously identified high grade G-CIMP and IDHmut-non-codel LGG cases split into LGm1 and LGm2-3. A methylation signature was able to discriminate a subgroup of IDHmut samples, which can be characterized as hypomethylated, displays activated expression of a cell cycle/cell proliferation signature and is enriched with SOX2-binding sites in the hypomethylated elements. Interestingly, this group can be characterized by worse clinical outcome. Likewise, among the IDHwt cohort, we observed distinct methylation and clinical subtypes with a subset with hypomethylated signature, showed an increased overall survival relative to both LGG and GBM IDHwt. Interestingly, this subtype lack mutation and copy number alterations compared to other IDHwt cases, and share a strong epigenetic profile similar to pilocytic astrocytoma. Our analyses were confirmed using 4 independent non-TCGA data and therefore suggests that new relevant subtypes of both IDHmut with poor survival and IDHwt with good survival exist and should be studied further.