Comparison between molecular and histological IDH-wild-type glioblastoma and extensive subgroup analysis of IDH-wild-type astrocytic tumors without genomic glioblastoma-defining alterations.
Summary
This study compared clinical characteristics and survival between molecularly defined IDH-wild-type glioblastoma (MolGBM) and histologically defined IDH-wild-type glioblastoma (HistGBM). It also characterized lower-grade IDH-wild-type astrocytic tumors lacking glioblastoma-defining genomic alterations. MolGBM exhibited a more favorable adjusted overall survival (HR 0.40) compared to HistGBM, particularly in patients aged 60 years or older. These findings highlight the clinical and biological heterogeneity among molecularly defined IDH-wild-type diffuse gliomas and the critical role of comprehensive molecular characterization. Lower-grade IDH-wild-type astrocytic tumors without glioblastoma-defining alterations warrant further in-depth molecular investigation.
Analysis
CLINICAL: This retrospective cohort study provides Level III evidence supporting the molecular classification of IDH-wild-type diffuse gliomas. It demonstrates that MolGBM is an independent prognostic factor for more favorable overall survival, particularly in patients aged 60 years and older. These findings reinforce the clinical utility of the 2021 WHO Classification of CNS tumors and could justify finer patient stratification in future clinical trials, potentially leading to adjustments in therapeutic strategies. Clinical impact could be seen in the medium term (3-5 years) by refining management protocols. BIOMOL: The study employed Sanger sequencing, whole-exome sequencing (WES), and DNA methylation profiling for molecular characterization. It identified TERT promoter mutation as a key marker for defining MolGBM, highlighting its role in classification and prognosis. The finding of diagnostic heterogeneity and longer survival in IDH-wild-type, TERTp-wild-type astrocytic tumors lacking glioblastoma-defining alterations underscores the need for comprehensive molecular characterization techniques for these subgroups. This could lead to the discovery of novel biomarkers or resistance mechanisms.