Genomic and chromosomal Instability: Hidden drivers of Glioblastoma aggressiveness

Glioblastoma is the most common and aggressive primary brain tumor in adults, characterized by rapid proliferation, diffuse infiltration, and poor clinical outcomes despite multimodal therapy. A hallmark of GBM biology is its remarkable genomic (GI) and chromosomal instability (CIN), which act as fundamental engines of tumor evolution. These processes fuel extensive intratumoral heterogeneity, drive the emergence of therapy-resistant clones, and contribute to immune evasion and disease recurrence. GI arises from replication stress, oxidative damage, and impaired DNA damage response pathways, while CIN encompasses large-scale chromosomal missegregation, aneuploidy, and structural rearrangements that perpetuate clonal diversity. Epigenetic deregulation and non-coding RNAs further modulate these mechanisms by altering the expression of oncogenes, tumor suppressors genes, and genome maintenance factors. Understanding the molecular underpinnings of GI and CIN in Glioblastoma, is crucial to elucidate the mechanisms driving its aggressiveness and therapeutic resistance. This review integrates recent advances on the origins and consequences of GI and CIN in GBM, underscores its prognostic and biological relevance, and discusses emerging therapeutic strategies that exploit these vulnerabilities to improve patient outcomes.