YBX1 Expression Marks Proliferative Tumour States with Context-Dependent Genomic Instability: A Pan-Cancer Analysis

Y-box binding protein 1 (YB-1; encoded by YBX1) is a multifunctional DNA- and RNA-binding protein implicated in cell cycle regulation, DNA repair, stress adaptation, and therapy resistance. Elevated YBX1 expression has been associated with aggressive disease across multiple cancer types; however, its pan-cancer genomic and clinical correlates, and the extent to which these reflect proliferative activity versus genomic instability, remain incompletely defined. Here, we performed an integrative pan-cancer analysis across 53 independent datasets spanning 33 tumour types, incorporating transcriptomic (YBX1 mRNA), proteomic (RPPA), genomic, and clinical data. We found that YBX1 is rarely altered at the genomic level, whereas its mRNA expression is highly variable within tumour cohorts. Tumours with high YBX1 mRNA expression consistently exhibited conserved transcriptional programmes enriched for cell cycle, mitotic, RNA processing, and signalling pathways, patterns that were also reflected at the protein level by concordant pathway associations with elevated YB-1 abundance. These molecular features co-occurred with clinicopathological characteristics indicative of aggressive disease. High YBX1 mRNA expression was associated with increased mutation burden, chromosomal alteration burden, hypoxia, and homologous recombination deficiency at the pan-cancer level, with similar molecular associations observed in tumours stratified by elevated YB-1 protein levels. The association between YBX1 expression and chromosomal alteration burden was largely attenuated after accounting for proliferative activity, particularly G2/M-associated transcriptional programmes used as a proxy for mitotic activity. While the relationship with mutation burden was heterogeneous across tumour types, this pattern suggests that links between YBX1 expression and chromosomal instability primarily reflect shared proliferative and mitotic tumour biology rather than an independent genomic instability programme. Clinically, high YBX1 mRNA expression was associated with advanced disease stage, higher histologic grade, reduced progression-free survival, and poorer overall survival. Elevated YB-1 protein levels were also associated with advanced disease stage and poorer survival outcomes and demonstrated a similar, although non-significant, directional trend with histologic grade. Collectively, these findings demonstrate that elevated YBX1 expression marks proliferative and clinically aggressive tumour states within which genomic instability-related features arise in a context-dependent manner, providing a clarified pan-cancer framework for interpreting YB-1-associated tumour biology.