ArticleActa neuropathologica communications2026
Histological grade 2 and non-contrast-enhancing phenotype provide prognostic information complementary to DNA methylation classification in TERTp-mutant molecular glioblastomas.
Article in Acta neuropathologica communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Glioblastoma (GBM), IDH-wildtype, is the most common and aggressive primary brain tumor in adults. According to the 2021 WHO classification, IDH-wildtype diffuse gliomas with a TERT promoter (TERTp) mutation, EGFR amplification, or combined whole-chromosome 7 gain and 10 loss (+ 7/− 10) are designated as GBM, IDH-wildtype, regardless of histological grade, and termed molecular GBM (mol-GBM). Although this redefinition has been widely adopted, the prognostic implications of mol-GBM remain uncertain. To clarify its clinical relevance, we retrospectively analyzed adult patients treated at our institution between 2010 and 2024. We identified 22 cases of TERTp-mutant mol-GBM (grade 2, n = 7; grade 3, n = 15) and compared them with 218 cases of TERTp-mutant histologically confirmed GBM (hist-GBM). Overall survival (OS) was assessed using Kaplan–Meier analysis, log-rank test, and propensity score matching (PSM) adjusted for age, preoperative Karnofsky Performance Status, extent of resection, adjuvant therapy, and MGMT methylation status. Mol-GBM showed significantly longer OS than hist-GBM after PSM (p = 0.019), with grade 2 mol-GBM showing particularly favorable survival (p = 0.008). Cox regression analysis revealed mol-GBM as an independent predictor of good prognosis (hazard ratio: 0.37, 95% confidence interval: 0.22–0.62, p < 0.001). Across all TERTp-mutant GBMs, a non-contrast-enhancing (non-CE) MRI phenotype correlated with significantly longer OS than CE tumors, persisting after PSM (p = 0.004). Within mol-GBM, an isolated TERTp mutation did not stratify OS, whereas CDKN2A/B homozygous deletion predicted worse outcomes (p = 0.026). DNA methylation profiling classified most mol-GBM as GBM, IDH-wildtype methylation class, and all cases clustered with GBM on t-SNE, confirming molecular proximity to GBM. Integrated methylation and RNA-seq analysis revealed WIF-1 promoter hypermethylation with reduced expression in grade 3 cases. These findings suggest that histological grade 2 and the non-CE phenotype may provide exploratory prognostic information in TERTp-mutant mol-GBM, complementary to DNA methylation classification.
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