Integrative Genomic and Transcriptomic Analysis Identifies BAX as a Prognostic Marker of Disease Progression in...

Background/Objectives: Prostate cancer is one of the most common malignancies among men worldwide, and clinical outcomes following androgen deprivation therapy (ADT) vary considerably. Given that endoplasmic reticulum (ER) stress and the unfolded protein response mediate processes such as apoptosis, tumor adaptation, and disease progression, we aimed to investigate whether genetic variants in ER stress-related genes are associated with survival outcomes in patients with prostate cancer receiving ADT. Methods: This study enrolled 630 patients with prostate cancer who underwent ADT across three medical centers in Taiwan. A genetic association analysis of 89 haplotype-tagged single-nucleotide polymorphisms (SNPs) across 12 ER stress-related genes was performed. The primary clinical endpoint was overall survival (OS). Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate prognostic associations. Furthermore, publicly available databases were integrated to analyze gene expression, clinical relevance, gene set enrichment, and tumor immune infiltration to elucidate the underlying biological mechanisms. Results: Among the analyzed SNPs, BAX rs182509214 showed the strongest association with OS. The minor G allele of BAX rs182509214 was significantly associated with poorer OS. Prostate tumor tissues exhibited markedly elevated BAX expression compared with normal prostate tissues, and this elevated expression was associated with worse survival outcomes. Multiple public gene expression datasets confirmed the overexpression of BAX in prostate cancer. Functional analyses revealed that genes associated with BAX expression were predominantly enriched in ribosomal, oxidative phosphorylation, and proteasomal pathways. Furthermore, the BAX copy number variation was significantly associated with the infiltration levels of multiple immune cell types, and BAX expression was negatively correlated with CD8⁺ T-cell infiltration, implying a potential marker role for the tumor immune microenvironment. Conclusions: The ER stress-related genetic variant, BAX rs182509214, may influence survival outcomes in patients with prostate cancer receiving ADT. BAX alterations are associated with disease progression and linked to mitochondria-related metabolic pathways and the tumor immune microenvironment. These results highlight BAX as a potential prognostic biomarker for prostate cancer treated with ADT; however, further validation in larger cohorts and functional studies is warranted.