Germline YAP1 rs1894116 Variation Predicts Improved Survival in ADT-Treated Prostate Cancer
Background
Prostate cancer progression is often managed with androgen deprivation therapy (ADT), but outcomes vary significantly, and identifying prognostic biomarkers remains a critical challenge. The Notch signaling pathway plays a complex, context-dependent role in various cancers, including prostate cancer, influencing cell proliferation, differentiation, and survival. However, the prognostic relevance of inherited genetic variations within Notch-related genes in men undergoing ADT has been largely unexplored, representing a significant gap in understanding personalized treatment responses and disease progression. This study aimed to elucidate how germline SNPs in this pathway impact survival in ADT-treated patients.
Study Design
Researchers genotyped 222 single-nucleotide polymorphisms (SNPs) across 24 Notch pathway-related genes in a cohort of 630 patients with advanced prostate cancer. The primary endpoints were cancer-specific survival (CSS) and overall survival (OS), assessed using Cox proportional hazards models. To investigate functional relevance, integrative bioinformatics analyses were performed, including pooled transcriptomic dataset analysis, expression quantitative trait locus (eQTL) analysis, and pathway enrichment to link genetic variation to gene expression and biological pathways.
Results
Multiple SNPs within the Notch pathway were significantly associated with both CSS and OS. The Yes1-associated transcriptional regulator (YAP1) rs1894116 exhibited the strongest prognostic signal. > The minor G allele of YAP1 rs1894116 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 YAP1 expression. Pooled transcriptomic analyses further revealed lower YAP1 expression in tumor tissues compared to normal tissue, while higher YAP1 expression consistently correlated with more favorable clinical outcomes. Genes correlated with YAP1 expression were significantly enriched in the focal adhesion pathway, particularly involving vinculin, suggesting a novel tumor-suppressive YAP1-focal adhesion axis.
Key Findings
- Germline
YAP1rs1894116 minor G allele linked to 26% reduced prostate cancer-specific mortality. YAP1rs1894116 minor G allele associated with 22% reduced all-cause mortality in ADT-treated patients.- Functional analysis suggests rs1894116 increases
YAP1expression. - Higher
YAP1expression correlated with more favorable outcomes in prostate cancer. YAP1-correlated genes are enriched in thefocal adhesion pathway, implicating a tumor-suppressive axis.
Why It Matters
Identifying germline genetic markers like YAP1 rs1894116 could enable personalized risk stratification and treatment optimization for prostate cancer patients receiving ADT. This finding suggests that individuals with the minor G allele might have a more favorable prognosis, potentially influencing treatment intensity or follow-up protocols. Furthermore, the study uncovers a novel tumor-suppressive role for YAP1 and its coordination with the focal adhesion pathway in prostate cancer, offering new mechanistic insights beyond the traditional Notch pathway understanding. This could pave the way for future therapeutic strategies targeting this YAP1-focal adhesion axis to improve outcomes.
prostate-cancer
adt
germline-variation
notch-pathway
yap1
focal-adhesion