PATH-05. Oligosarcoma characteristically exhibits a HOX gene hypermethylation signature

Abstract Recent converging studies from multiple independent groups have demonstrated that a subset of clinically aggressive IDH-mutant gliomas harbor abnormal methylation patterns among the developmentally-regulated HOX gene family members. More specifically, our group has previously shown that a large subset of oligodendroglioma, IDH-mutant and 1p/19q are characterized by pan-HOX gene body hypermethylation signature. Oligosarcoma is a recently described aggressive IDH-mutant glioma subtype with its own distinct histological and DNA methylation features. Currently, any potential association between HOX gene methylation status and oligosarcoma is unknown. To address this gap in knowledge, we analyzed HOX gene methylation patterns across 52 methylation-defined oligosarcomas. We batch corrected the idat files of these 52 oligosarcomas in parallel with 284 oligodendrogliomas, and performed dimensionality reduction based gene body methylation probes for 39 HOX gene family members as previously described. Dimensionality reduction by UMAP confirmed our previous findings that oligodendrogliomas can be separated into two distinct groups, a HOX-high methylation group and a HOX-low methylation group. Oligosarcomas uniformly group near the HOX-high oligodendroglioma cluster with bootstrapping demonstrating overlap between these groups over 1000 iterations. Pan-HOX gene body methylation is significantly higher in the oligosarcoma group compared to the HOX-low oligodendroglioma group. Next, we analyzed five paired tumor samples, where the initial tumor was characterized as an oligodendroglioma and the subsequent clinically recurrent tumor was characterized as progression to oligosarcoma. Four of the five initial oligodendrogliomas were characterized as HOX-low tumors; three of which had increased HOX methylation with progression to oligosarcoma. In summary, oligosarcomas demonstrate a HOX gene body hypermethylation signature, similar to the aggressive HOX-high subset of oligodendrogliomas previously reported.