Elevated YBX1 mRNA expression is associated with a genomically unstable and clinically aggressive cancer state: a pan-cancer analysis

Abstract Y-box binding protein 1 (YB-1; YBX1) is a multifunctional DNA- and RNA-binding protein involved in cell cycle regulation, DNA repair, stress adaptation, and therapy resistance. Elevated YBX1 mRNA expression is associated with aggressive disease across multiple cancers, yet its pan-cancer genomic and clinical correlates remain unclear. Here, we performed a comprehensive pan-cancer analysis across 53 datasets spanning 33 tumour types, integrating RNA expression, somatic mutations, copy number, hypoxia, and clinical outcomes. YBX1 was rarely mutated or amplified, indicating that oncogenic relevance is primarily driven by its expression. Tumours with high YBX1 mRNA exhibited a conserved transcriptional program enriched for cell cycle, DNA repair, and chromatin regulation pathways, and were preferentially mutated in genes involved in maintaining genomic stability, including TP53. These tumours were associated with increased mutation burden, fraction of genome altered, homologous recombination deficiency, and elevated hypoxia. Clinically, high YBX1 mRNA associated with advanced stage, higher grade, shorter progression-free survival, and reduced overall survival. Collectively, high YBX1 mRNA expression defines a conserved, genomically unstable, and clinically aggressive tumour state across multiple cancer types.