ZIC3 expression identifies a developmental transcriptional axis in IDH-wildtype glioblastoma

Area of Science:

• Neuro-oncology
• Cancer genomics
• Molecular biology

Background:

• IDH-wildtype glioblastoma is highly heterogeneous, with poorly understood molecular drivers of distinct tumor states.
• Current classifications do not fully capture the dynamic cellular states influencing glioblastoma progression.

Purpose of the Study:

• To investigate if ZIC3 gene expression can identify a specific transcriptional state in IDH-wildtype glioblastoma.
• To determine if this ZIC3-defined state correlates with patient clinical outcomes.

Main Methods:

• Analysis of RNA sequencing and clinical data from The Cancer Genome Atlas (TCGA) glioblastoma cohort (n=167 IDH-wildtype tumors).
• Survival analyses using Cox regression and Kaplan-Meier methods (n=161 patients).
• Evaluation of ZIC3 expression association with MGMT methylation, tumor microenvironment, and single-cell RNA sequencing data.

Main Results:

• Higher ZIC3 expression correlated with significantly longer overall and progression-free survival in IDH-wildtype glioblastoma.
• ZIC3 expression was not linked to MGMT promoter methylation or standard tumor microenvironment scores.
• ZIC3-high tumors showed enrichment of neural lineage and blood-brain barrier programs, while ZIC3-low tumors exhibited hypoxia and metabolic stress pathways.

Conclusions:

• ZIC3 expression defines a developmental transcriptional axis in IDH-wildtype glioblastoma.
• This axis connects neural lineage programs with hypoxia-adaptive tumor states, offering insights into glioblastoma heterogeneity and progression.