HGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT HIGH GRADE GLIOMAS

Abstract Replication repair deficiency (RRD) is an important driving mechanism of pediatric high grade glioma (pHGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although pHGG present specific patterns of DNA methylation corresponding to driving oncogenic processes, methylation patterns have not been well studied in RRD tumors. We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic or epigenetic mechanisms and 10 additional pHGG samples known to be hypermutant. RRD pHGG displayed a methylation pattern corresponding to specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD pHGG lacking these known secondary mutations largely clustered together with a poorly described group previously labelled Wild type-C. Most of the hypermutant tumors clustered in a similar location suggesting undiagnosed RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at gene promotors. Prominent demethylation was observed in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.