GENO-19INTEGRATED GENOMIC ANALYSIS OF OLIGODENDROGLIAL TUMORS IDENTIFIES DISTINCT MOLECULAR SUBGROUPS WITHIN 1p/19q CO-DELETED OLIGODENDROGLIOMAS

BACKGROUND: Oligodendroglial tumors are a group of heterogeneous gliomas in terms of clinical, radiological, histological and molecular profiles. Current molecular classification of oligodendroglial tumors identifies 3 groups with distinct clinical outcomes based on two genetic events only: IDH mutation and 1p/19q co-deletion. Integrating data from additional molecular level contributes to refine further this classification and adapt clinical practice accordingly. METHODS: 156 tumors with an oligodendroglial component (Grade II(46), III(100), IV(10)) as well as 22 supportive samples (11 glioblastomas, 2 diffuse astrocytomas, 9 normal brain samples) were profiled transcriptionally (mRNA expression arrays and microRNA sequencing), genomically (SNP arrays) and epigenetically (DNA methylation arrays). Unsupervised consensus classification was performed for each omics separately and by integrating the different omics. RESULTS: A strong correlation was observed between the classification systems obtained from the different omics and 5 subgroups of tumors were robustly identified. The validity of these 5 classes was confirmed on public TCGA data from low grade gliomas (TCGA-LGG). Beyond the 3 well-known molecular classes (1p/19q co-deletion and IDH mutation, IDH mutation only, no IDH mutation and no 1p/19q co-deletion), our multi-omics classification reveals 3 additional subgroups within the group of 1p/19q co-deleted tumors. These 3 subgroups are associated with distinct genomic alterations, distinct expression patterns of cell differentiation markers (from oligodendroglial precursor cells, oligodendrocytes, or neuronal cells), and distinct expression of oncogenic pathways and immune signatures. Follow-up duration of our cohort was not long enough to highlight reliable associations with prognosis but the analysis of TCGA-LGG based on our new 3 subgroups shows a significant association with distinct survival outcomes independently from histologic grade. CONCLUSION: This work represents the first integrative multi-omics analysis of oligodendroglial tumors and enables the refining of their molecular classification. The new classification identifies for the first time distinct molecular subgroups within 1p/19q co-deleted oligodendroglial tumors.