TP53 Mutation Heterogeneity Refines Prognostic Stratification in IDH ‐Wildtype Glioma

ABSTRACT Clinically, TP53 mutation ( TP53 ‐mut) has long been simplistically dichotomized as mutant versus wildtype, overlooking their structural and functional complexity. The prognostic significance of TP53 ‑mut in IDH ‑wildtype ( IDH ‑wt) gliomas remains controversial. In 237 IDH ‑wt gliomas, we integrated clinical, genomic, and follow‑up data to test whether mutation subtypes refine risk stratification. In this cohort, 73 patients (73/237, 30.8%) harbored TP53 ‐mut, which was significantly associated with worse overall survival. Subgroup analysis further revealed that patients with mutations in the β‑strand region had a median outcome of only 12.0 months, markedly inferior to those with mutations in the α‑helix (22.5 months), loop (23.9 months), and turn/other regions (23.6 months). Multivariable Cox regression analysis showed that TP53 ‐mut was an independent prognostic factor associated with worse outcome (HR = 1.91; 95%CI: 1.29–2.84; p =  0.001). Notably, TP53 ‑mut patients with variant allele frequency (VAF)≥10% showed significantly worse survival than those with VAFp =  0.030), whereas VAFTP53 ‑wt. In addition, p53 immunohistochemistry score≥4 yielded an area under the curve (AUC) of 0.79 for TP53 ‐mut prediction. Collectively, TP53 ‐mut in IDH ‑wt gliomas are prognostically heterogeneous. A VAF≥ 10% identified a potential high‑risk subgroup, with β‐strand mutations associated with the poorest survival in our cohort. p53 immunohistochemistry offers a cost‑effective surrogate screen.