Distinct molecular profiles characterize the spontaneous growth rate of IDHmt low-grade astrocytomas and oligodendrogliomas

Background: The life expectancy of patients with diffuse IDH-mutant low-grade gliomas (IDHmt LGG) ranges from 5 to over 20 years. Tumor behavior, including spontaneous growth rate, varies even within homogeneously classified subtypes of oligodendroglioma and astrocytoma. Risk-adjusted treatment strategies are needed to avoid therapy-related toxicities without compromising outcome. The spontaneous tumor volume growth rate (TVGR) serves as a prognostic marker and predicts response to therapy. Accurate prediction of TVGR through biomarkers would enable improved evidence-based risk management. Patients and methods: A cohort of 77 patients treated in Montpellier, France, for IDHmt LGG grade II (WHO 2016) (29 oligodendrogliomas and 48 astrocytomas) was constituted (age >18 years; MRI scans, frozen tumor tissue). The DNA methylome (Illumina, EPIC array) and transcriptome (RNAseq) were established. TVGR was determined based on serial MRIs collected over the "watch & wait" period before the first treatment beyond surgery. Transcriptomic and methylome data were analyzed for signatures associated with TVGR using rank-rank regression followed by preranked gene set enrichment analysis. Results: The median TVGR was lower in IDHmt codeleted compared to non-codeleted LGG (0.241 year-1 range 0.082-0.366 vs. 0.424 year-1 range 0.264-0.609, P < .001). In codeleted IDHmt LGG, TVGR was associated with upregulated gene signatures for neuronal systems, synaptic activity, and activation of repressed or poised signatures of neural progenitor cells, while the TVGR in non-codeleted IDHmt LGG was dominated by upregulated proliferation-related signatures, including DNA replication and repair. Conclusion: Spontaneous TVGR of codeleted and non-codeleted IDHmt LGG involves distinct biological processes, suggesting possible differences in response to therapies.