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Integrative Transcriptomic and Perturbagen Analyses Reveal Sex-Specific Molecular Signatures Across Glioma Subtypes.

Madhu Vishnu Sankar Reddy Rami Reddy1,2, Jacob F Wood1,2, Jordan Norris1,2

  • 1Department of Neurosciences and Psychiatry, The University of Toledo College of Medicine, Toledo, OH 43614, USA.

Cancers
|January 10, 2026
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Summary

Biological sex influences glioma progression, with distinct gene expression patterns observed between males and females. Findings support sex-specific therapeutic strategies for glioma treatment.

Keywords:
GBMbioinformaticsdrug identificationglioblastomatranscriptomics

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Area of Science:

  • Neuro-oncology
  • Genomics
  • Translational Medicine

Background:

  • Biological sex is increasingly recognized as a factor influencing glioma biology and treatment outcomes.
  • Understanding sex-specific differences in glioma is crucial for developing effective therapies.

Purpose of the Study:

  • To perform a sex-stratified analysis of glioma RNA sequencing data to identify sex-specific molecular alterations during malignant transformation.
  • To explore potential therapeutic strategies and biomarkers based on sex-specific glioma pathways.

Main Methods:

  • Sex-stratified differential gene expression analysis of Chinese Glioma Genome Atlas (CGGA) RNA sequencing data comparing low-grade glioma (LGG) with high-grade glioma (HGG) and glioblastoma (GBM).
  • Integration of differential expression analysis with Gene Set Enrichment Analysis (GSEA), EnrichR, leading-edge analysis, and iLINCS drug repurposing using the 3PodR framework.
  • Identification of sex-specific differentially expressed genes (DEGs) and pathway enrichment analysis.

Main Results:

  • Significant sex-specific differences in DEGs were observed between LGG vs. HGG and LGG vs. GBM comparisons, with a notable percentage of unique DEGs per sex.
  • Both sexes shared enrichment of neuronal and synaptic programs, including glutamatergic receptor genes.
  • Females exhibited downregulation of mitotic and chromosome-segregation programs, while males showed reduced extracellular matrix and immune-interaction pathways.
  • Gene-level contrasts revealed sex-specific expression patterns for genes such as GLI1, GCGR, MYOD1, and HIST1H2BH.

Conclusions:

  • Glioma grade progression involves a shared neuronal-synaptic program alongside sex-specific transcriptional remodeling.
  • Findings advocate for sex-aware therapeutic strategies targeting neuron-glioma interactions and specific molecular pathways (e.g., chromatin, receptor tyrosine kinase/angiogenic).
  • Biomarkers including GLI1, MYOD1, GCGR, PRLHR, and HIST1H2BH are nominated for future validation in sex-specific glioma treatment approaches.