The clinical and molecular landscape of thalamic glioma.

BACKGROUND: Thalamic gliomas (TGs) remain a formidable clinical challenge for accurate diagnosis and effective therapy. This study aims to refine molecular diagnosis and surgical management of TGs by integrating clinicopathological and multi-omics data. METHODS: We analyzed 106 TGs, comprising 65 diffuse midline glioma (DMG) and 41 non-DMG, using genomic profiling, single-cell RNA sequencing, and orthogonal assays. Surgical outcomes were evaluated using rigorous causal inference frameworks, including propensity score matching and difference-in-differences analyses. RESULTS: Genomic profiling revealed striking mutual exclusivity between H3F3A mutations and CDKN2A/B (9p21) loss. Single-cell and orthogonal assays validated that 9p21 loss emerged as a highly specific adjunctive marker favoring non-DMG over DMG. Causal inference analyses consistently demonstrated that microsurgical third ventriculostomy (mTV) confers profound protection against postoperative hydrocephalus (risk reduction > 60%). Multivariate analysis identified the transfrontal approach as an independent predictor of postoperative motor deficits. Survival analysis showed that the median overall survival of this cohort following surgical resection was 21.0 months. Extent of resection and tumor mutational burden emerged as the principal independent determinants of prognosis, whereas postoperative KPS showed survival stratification in univariable/subgroup analyses but was not independently significant in multivariable model. CONCLUSIONS: In this 106-patient cohort study, we delineated the somatic mutational landscape of thalamic glioma and showed that 9p21 loss is mutually exclusive with H3F3A mutations, providing a highly specific adjunctive marker for thalamic glioma. We further demonstrated that maximal surgical resection confers a survival benefit and intraoperative mTV serves as a standardized treatment workflow to optimize care for thalamic glioma.