Unveiling DENND2D as a Novel Prognostic Biomarker for Prostate Cancer Recurrence: From Gene to Prognosis

<b>Background:</b> Prostate cancer is a major global health burden, with biochemical recurrence (BCR) following radical prostatectomy affecting 20-40% of patients and posing significant challenges to prognosis and treatment. Emerging evidence suggests a critical role for differentially expressed in normal and neoplastic cell (<i>DENN</i>) domain-containing genes in oncogenesis; however, their implications in prostate cancer and BCR risk remain underexplored. <b>Methods:</b> This study systematically evaluated 151 single-nucleotide polymorphisms in <i>DENN</i> domain-containing genes in 458 patients with prostate cancer and BCR, followed by validation in an independent cohort of 185 patients. <b>Results:</b> Multivariate Cox regression analyses identified <i>DENND2D</i> rs610261 G>A as significantly associated with improved BCR-free survival in both cohorts (adjusted hazard ratio = 0.39, 95% confidence interval = 0.23-0.66, <i>p</i> = 0.001). Functional analysis revealed rs610261's regulatory potential, with the protective A allele correlating with increased <i>DENND2D</i> expression in various human tissues. Compared to normal prostate tissues, <i>DENND2D</i> expression was reduced in prostate cancer, with higher expression being linked to favorable patient prognosis (<i>p</i> = 0.03). Gene set enrichment analysis revealed an association between <i>DENND2D</i> expression and the negative regulation of <i>MYC</i> target genes, including <i>MAD2L1</i>, <i>ERH</i>, and <i>CLNS1A</i>, which are overexpressed in prostate cancer and associated with poor survival. Furthermore, the elevated <i>DENND2D</i> expression promotes immune infiltration in prostate cancer, supporting its role in immune modulation. <b>Conclusions:</b><i>DENND2D</i> is a prognostic biomarker for BCR in prostate cancer and offers new avenues for personalized treatment strategies.