Germline Variation in Notch Pathway and Survival After Androgen Deprivation Therapy in Prostate Cancer: Implicating <i>YAP1</i> rs1894116 and Focal Adhesion Signaling

<h3>Abstract</h3> <h3>Background/Aim:</h3> Notch signaling exerts context-dependent effects in cancer; however, the prognostic relevance of inherited variation in Notch-related genes in prostate cancer remains unclear. We investigated whether germline single-nucleotide polymorphisms (SNPs) in Notch pathway genes are associated with clinical outcomes in men receiving androgen deprivation therapy (ADT). <h3>Patients and Methods:</h3> We genotyped 222 SNPs across 24 Notch pathway-related genes in 630 patients with advanced prostate cancer. Associations with cancer-specific survival (CSS) and overall survival (OS) were assessed using Cox proportional hazards models. Integrative bioinformatics analyses, including pooled transcriptomic dataset analysis, expression quantitative trait locus analysis, and pathway enrichment, were performed to assess functional relevance. <h3>Results:</h3> Multiple SNPs were significantly associated with CSS and OS, with Yes1-associated transcriptional regulator (<i>YAP1</i>) rs1894116 showing the strongest prognostic signal. The minor G allele was associated with a 26% reduction in prostate cancer-specific mortality and a 22% reduction in all-cause mortality, independent of established clinical predictors. Functional annotation suggested that rs1894116 may be linked to increased <i>YAP1</i> expression. Pooled transcriptomic analyses showed lower <i>YAP1</i> expression in tumors than in normal tissue, while higher <i>YAP1</i> expression correlated with more favorable outcomes. <i>YAP1</i>-correlated genes were enriched in the focal adhesion pathway, suggesting a tumor-suppressive <i>YAP1</i>-focal adhesion axis, particularly involving vinculin. <h3>Conclusion:</h3> Germline variation in the Notch–YAP axis, notably <i>YAP1</i> rs1894116, predicts survival in patients with prostate cancer treated with ADT. Elevated <i>YAP1</i> expression and coordinated activation of focal adhesion components may be associated with less aggressive disease. These findings provide mechanistic insight into Notch signaling in prostate cancer and highlight <i>YAP1</i> and its variants as potential biomarkers for risk stratification and personalized therapy.