Gliomas display distinct sex-based differential methylation patterns based on molecular subtype

Area of Science:

• Neuro-oncology
• Epigenetics
• Genomics

Background:

• Gliomas are common primary brain tumors with higher incidence in males.
• Limited understanding of sex-based molecular differences in glioblastoma (GBM) and non-GBM glioma subtypes.
• DNA methylation, an epigenetic mechanism, influences gene transcription and patient outcomes in cancer.

Purpose of the Study:

• To investigate sex-based DNA methylation differences across various glioma molecular subtypes.
• To determine if epigenetic alterations vary between males and females in glioma.

Main Methods:

• Utilized The Cancer Genome Atlas data for molecular and clinical information from glioma patients.
• Grouped patients by tumor grade and molecular subtype (IDH1/2 mutation, 1p/19q deletion).
• Identified sex-specific differentially methylated probes (DMPs) and regions (DMRs), and analyzed associated DNA-binding motifs.

Main Results:

• Discovered unique sex-specific DMPs and DMRs in each of the 4 analyzed glioma subtypes.
• Motif analysis revealed distinct sex-based DNA-binding motifs varying by glioma subtype.
• Downstream targets of GBM-specific transcription factors (NFAT5, KLF6) showed differential gene expression linked to methylation-mediated downregulation.

Conclusions:

• Sex-based DNA methylation differences are present in 4 glioma molecular subtypes.
• These findings indicate a significant, sex-specific role for DNA methylation in the epigenetic regulation of gliomagenesis.
• Highlights potential sex-specific molecular mechanisms contributing to brain tumor development.