Os04.4.a long- and short-term survivors among adult patients with diffuse who grade 2-3 glioma: clinical features, molecular reclassification and dna methylation patterns

Abstract BACKGROUND Diffuse gliomas show considerable heterogeneity in terms of survival. The WHO classifications of 2016 and 2021 improved prognostic stratification due to the definition of biologically and clinically homogeneous tumor entities. However, further prognostic models considering clinical and molecular factors are needed to balance survival benefit with adverse treatment-related long-term effects in therapeutic decisions. MATERIALS AND METHODS Patients with diffuse gliomas of WHO grades 2 and 3 diagnosed in 2000 - 2019 have been included. Long term survivors (LTS) were defined as patients with an overall survival (OS) of >10 years after radiological diagnosis, whereas short-term survivors (STS) had an OS of <1 year. Histological diagnosis was performed by a board-certified neuropathologist. DNA methylation analysis of formalin-fixed, paraffin-embedded tumor tissue was conducted using the Illumina EPIC 850k platform. The Heidelberg Methylation Classifier was applied to obtain methylation-based diagnoses. RESULTS Of 697 patients with WHO grade 2 and 3 glioma, 182 (26.1%) were LTS, and 42 (6.0%) were STS. LTS were younger than STS (median age: 36 vs. 59.5; p<0.001) and had a higher Karnofsky Performance Score at diagnosis (median: 90% vs. 80%; p<0.001). LTS more frequently presented with epileptic seizures (p<0.001), while more STS had motoric (p<0.001), sensory (p=0.021), and visual deficits (p=0.027) as well as aphasia (p<0.001) and behavioral changes (p=0.009). Histological diagnoses (including pre-2016) showed astrocytic histology in 117 (70.9% LTS, 29.1% STS), oligodendroglial in 61 (93.4% LTS, 6.6% STS), oligo-astroglial in 43 (97.7% LTS, 2.3% STS) and not otherwise specified in 3 (all STS; p<0.001). Molecular reclassification of pre-2016 diagnoses (n = 143) yielded divergent entities in 46 (32.2%) cases. Overall, integrated molecular diagnoses included astrocytoma (isocitrate dehydrogenase [IDH]-mutant] in 65 patients (95.4% LTS and 4.6% STS), oligodendroglioma (IDH-mutant, 1p/19q-codeleted) in 64 patients (98.4% LTS and 1.6% STS), IDH-wildtype gliomas in 24 patients (100% STS), anaplastic pilocytic astrocytoma in 2 STS, diffuse midline glioma (H3K27-altered) in 1 STS, and dysembryoplastic neuroepithelial tumor in 1 LTS, while not otherwise specified diagnoses were found in 4 patients (75% LTS, 25% STS; p<0.001). Unsupervised clustering based on DNA methylation profiling revealed two major clusters consisting of IDH-wildtype STS (cluster A) and IDH-mutant patients (cluster B; 94.6% LTS, 5.4% STS). In cluster B, one subcluster (n = 8) contained 3/4 IDH-mt STS. Further analyses of these cases including validation with publicly available DNA methylation data are ongoing. CONCLUSION LTS and STS show distinct clinical and molecular features. Further profiling of cases with divergent survival could provide more refined prognostic stratification.