Clinical characteristics, molecular reclassification trajectories and DNA methylation patterns of long- and short-term survivors of WHO grade II and III glioma

Purpose The prognosis of diffuse gliomas previously classified as "lower-grade" is heterogeneous and complicates clinical decisions. We aimed to investigate the molecular profile of clinical outliers to gain insight into biological drivers of long and short-term survivors. Methods Here, patients aged >= 18 years and diagnosed with diffuse glioma, WHO grade II/2 or III/3 were included. Short-term survivors (STS) were defined as overall survival (OS) < 1 years, and long-term survivors (LTS) as OS > 10 years. DNA methylation profiling was performed using the Illumina EPIC 850k platform. Results In total, 385 patients (294 LTS, 91 STS) were included. Median overall survival was 234 months (95%CI: 207-248) in LTS and 7.3 months (95%CI: 6.4-8.1) in STS. Compared to STS, LTS were younger, had higher Karnofsky Performance Status, more extensive resections, and lower symptomatic burden (p < 0.001, respectively). Molecular reclassification showed IDH-mutant gliomas in 240/246 (95.5%) LTS and 10/79 (12.7%) STS. Initial diagnosis (tumor type and/or grading) changed in 69/325 (21.2%) patients based on reclassification according to WHO 2016 and in 45/258 (17.4%) as per WHO 2021. DNA methylation analysis indicated two clusters, one with mainly STS (39/41, 95.1%) and heterogeneous IDH-wildtype tumors (cluster A) and one with mainly LTS (82/106, 77.4%) and IDH-mutant tumors (cluster B). Functional enrichment analysis of rare subtypes indicated altered Hippo/Notch and synaptic/neurotransmitter signaling pathway members. Conclusion LTS and STS show distinct clinical and molecular features, underscoring the importance of extended molecular workup for diagnosis. Further characterization of rare subtypes is needed to optimize treatment strategies and clinical trial planning.