Gene regulatory network analysis identifies dysregulation of hypoxia pathways as contributing to glioblastoma treatment resistance in females

BACKGROUND: Glioblastoma or GBM (IDH wild-type) is an aggressive brain tumor that is notoriously resistant to treatment, with an average survival time of 17 months. While the overall outcome is poor for both males and females, sex differences in GBM incidence and outcome suggest sex-specific biological mechanisms underlie tumorigenesis. In contrast, low-grade glioma (LGG) is a less aggressive brain tumor that tends to have a better prognosis and a longer survival time. METHODS: To understand mechanisms contributing to treatment resistance in GBM in both males and females, we inferred gene regulatory networks (GRNs) for males and females with LGG and GBM using RNA-seq data from The Cancer Genome Atlas (TCGA). We analyzed these to identify both sex-specific and sex-stratified gene regulation in GBM. We then validated these results on a separate cohort, the Repository of Molecular BRAin Neoplasia DaTa (REMBRANDT). RESULTS: We found sex-specific differential targeting of several pathways, including hypoxia and related pathways (carbohydrate metabolism, innate immune processes, and extracellular matrix pathways) known to be dysregulated in hypoxic conditions, in GBM when compared against LGG. After further evaluating the co-regulation of sex-specific pathways in GBM, we found that females exhibited a greater degree of co-regulation between hypoxia and hypoxia-associated transcriptional programs with the aforementioned downstream pathways than did males. CONCLUSIONS: Our results suggest that dysregulation of hypoxia-related pathways in GBM plays a female-specific role in resistance to treatment and overall outcomes.