P05.24.B DISTINCT MOLECULAR PROFILES CHARACTERIZE THE NATURAL GROWTH RATES OF IDHMT CODELETED AND NON-CODELETED DIFFUSE LOW-GRADE GLIOMA WHO GRADE 2 (OLIGODENDROGLIOMA AND ASTROCYTOMA)

Abstract BACKGROUND The life expectancy of patients with diffuse IDH-mutant low-grade gliomas (IDHmt LGG) WHO grade 2 varies greatly between 5 to over 20 years. Therefore, it is of importance to offer risk-adapted treatment strategies avoiding therapy related toxicities with the aim to best preserve cognitive and social function and quality of life, without compromising outcome. Maximal safe surgical resection is usually the first line treatment. However, the timing and choice of further treatments are debated. A “wait & watch” strategy is often adopted after tumor resection that ends when clinical and/or radiological criteria suggest progression and additional treatments are initiated. Biomarkers predicting the natural course of tumor growth, progression, and response to therapy would allow evidence-based risk management with adapted treatment strategies. MATERIAL AND METHODS A cohort of patients treated in Montpellier, France, for IDHmt LGG was constituted (age >18 years; availability of MRI scans during the “watch and wait” period and frozen tumor tissue). The DNA methylome (Illumina, EPIC array) and transcriptome (RNA sequencing) were established. The spontaneous tumor volume growth rate (TVGR) was determined based on MRI data collected over the “watch and wait” period up to the time of chemotherapy initiation. Pathways associated with the TVGR were determined based on the transcriptome and the DNA methylome using rank-rank regression followed by preranked gene set enrichment analysis-based Monte-Carlo procedure (GSEA, R packages msigdbr, ClusterProfiler) and MSigDB (v7.5.1, updated 2022 collections of H hallmark genes sets and C2). RESULTS Overlapping data was available for 77 patients (29 oligodendrogliomas, 48 astrocytomas). The median TVGR was lower in IDHmt codeleted LGG than for the non-codeleted, as expected (0.224 cm3/year, range 0.076-0.366 vs 0.402 cm3/year, range 0.178-0.597, p<0.001 (Wilcoxon’s test)). Association of the TVGR of the codeleted IDHmt LGGs with the transcriptome revealed upregulated gene signatures reflecting pathways such as signal transduction (e.g. across synapses), neuronal system, growth factor stimulation, hypoxia, and epigenetic features of neural progenitor cells and stem cells. In contrast, in non-codeleted IDHmt LGG upregulated gene sets were dominated by proliferation related pathways, such as cell cycle, DNA repair, DNA replication, and transcription. Few pathways emerged from functional methylation, reflecting development, differentiation and oligodendrocyte markers in the codeleted IDHmt LGG, and DNA repair, brain aging and oligodendrocyte differentiation in the non-codeleted. CONCLUSION Taken together, this suggests that the TVGRs of the natural evolution of codeleted and non-codeleted IDHmt LGG are associated with distinct biological processes. This implies that they may respond differentially to therapies.