Prognostische Implikationen molekularer Merkmale bei IDH-Wildtyp-Astrozytomen: eine vergleichende Analyse von molekularen und klassischen Glioblastomen

The 2021 CNS classification introduced the identification of glioblastoma (GBM) in histologically low-grade but IDH wild-type (IDH-WT) astrocytomas that exhibit a TERT promoter (TERTp) mutation. This study aims to evaluate the outcomes of histologically low-grade astrocytomas with molecular high-grade features (referred to as molecular GBM) and compare their outcomes to those of patients with histologically "classical" GBM.

We analyzed 48 tumor samples from patients with IDH-WT histologically low-grade astrocytomas (WHO grades 2–3, molecular GBM cohort) and compared them to 55 patients with classical GBM (classical GBM cohort). Molecular profiling was conducted using whole-exome and Sanger sequencing. Data on progression-free survival (PFS), overall survival (OS), and tumor characteristics were collected and analyzed across the two cohorts.

In the molecular GBM cohort (20 females and 28 males), 75% of tumors (n=36) harbored a TERTp mutation (TERTp-mut), while 25% (n=12) were TERTp wild-type (TERTp-WT). The median age at diagnosis for this cohort was 67 years (range: 24–86 years), with a median OS of 20 months and PFS of 15 months. TERTp status did not correlate with age at diagnosis (TERTp-mut: 67 years; TERTp-WT: 61 years). However, TERTp-mut patients had significantly shorter OS (19 months) compared to TERTp-WT patients (56 months; p=0.0003). Remarkably, TERTp-WT astrocytoma were enriched with ATRX and NF1 mutations (n= 5/12, 41.6%). The classical GBM cohort consisted of 22 females and 33 males, with 76.3% of tumors (n=42) harboring a TERTp mutation, while 23.7% were classified as TERTp-WT (n=13). The median age at diagnosis was 57.8 years (range: 33-79 years), with a median OS of 13.2 months. When comparing outcomes between cohorts, OS in molecular GBM patients with TERTp-mut (19 months) was similar to that of classical GBM patients with TERTp-mut (13.2 months). However, TERTp-WT patients in the molecular GBM cohort demonstrated significantly longer OS (56 months) compared to TERTp-WT patients in the classical GBM cohort (14.3 months; p=0.0013).

Our findings confirm that the presence of a TERTp mutation is consistently associated with poor survival in IDH wild-type gliomas, regardless of histological appearance. In contrast, IDH-WT/TERTp-WT astrocytomas with low-grade histological features exhibit significantly better OS compared to TERTp-WT classical GBM. These results highlight the heterogeneity within IDH-WT gliomas.