Abstract 7564: DNA methylation profiling identifies two distinct groups of oligosarcoma, IDH-mutant with distinct genetic alterations and clinical outcomes

Abstract DNA methylation has been extensively adopted for the classification of brain tumors and is endorsed by current neuropathology guidelines. Recently, oligosarcoma, IDH-mutant has been characterized as a distinct group of IDH mutant gliomas by DNA methylation classification. However, emerging studies revealed the variety in this group. Here, we employed DNA methylation-based t-SNE analysis to characterize oligosarcomas identified by the dkfz brain tumor classifier (v12.5). Thereby, we uncovered that oligosarcomas were segregated into two distinct groups, namely, subgroup A and subgroup B, which were further validated by genetic alterations and clinical outcomes. Next-generation Sequencing revealed subtype A tumors enriched with chr 1p/19q co-deletion, chr 6q loss, CDKN2A/B homogeneous deletion, TERT promoter mutation, and NF1 mutation, while subtype B tumors showed chr7 gaining and TP53 mutation. RNA sequencing and gene set enrichment analysis (GSEA) revealed that neuronal-tumor interaction and muscular progression pathways were more enriched in subtype A tumors. In contrast, subtype B tumors showed enrichment for angiogenesis and mTOR pathways. Additionally, inter-chromosomal fusion genes were more frequently found in subtype A tumors. Clinically, patients with subgroup A oligosarcomas manifested poorer survival and distinct imaging features in magnetic resonance imaging (MRI) compared to those with subgroup B. Collectively, we provided more cases of oligosarcoma, IDH-mutant, confirming the existence of this newly identified group, and revealed the subgroups harboring different genetic alterations and suffering different prognoses, providing new evidence for the molecular pathology in diffuse glioma. Citation Format: Kenan Zhang, Lingyu Liu, Xing Liu, Tao Jiang. DNA methylation profiling identifies two distinct groups of oligosarcoma, IDH-mutant with distinct genetic alterations and clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7564.