Differences in methylation profiles between long-term survivors and short-term survivors of IDH- wildtype glioblastoma

Patients with glioblastoma (GBM) have a median overall survival (OS) of approximately 16 months. However, approximately 5% of patients survive >5 years. This study examines the differences in methylation profiles between long-term survivors (>5 years, LTS) and short-term survivors (<1 year, STS) with isocitrate dehydrogenase (IDH)-wildtype GBMs. In a multicenter retrospective analysis, we identified 25 LTS with a histologically confirmed GBM. They were age- and sex-matched to a STS. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of LTS versus STS were compared. After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH-wildtype GBMs, all with +7/-10 signature. LTS had significantly increased MGMT promoter methylation, and higher prevalence of FGFR3-TACC3 fusion (p=0.03). STS were more likely to exhibit CDKN2A/B loss (p=0.01) and higher frequency of NF1 (p=0.02) mutation. There were no significant CpGs identified between LTS vs STS at an adjusted p-value of 0.05. Unadjusted analyses identified key pathways involved in both LTS and STS. The most common pathways were the Hippo signaling pathway and the Wnt-pathway in LTS, and GPCR ligand binding and cell-cell signaling in STS. A small group of patients with IDH-wildtype GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.