Interplay Between Type 2 Diabetes Susceptibility and Prostate Cancer Progression: Functional Insights into C2CD4A

<b>Background/Objective:</b> Biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer indicates disease progression. Although type 2 diabetes mellitus (T2D) shows a paradoxical association with prostate cancer risk, the prognostic role of T2D-related genetic variants remains unclear. <b>Methods:</b> We analyzed 113 common T2D susceptibility-related single-nucleotide polymorphisms (SNPs) in 644 Taiwanese men with localized prostate cancer (D'Amico risk classification: 12% low, 34% intermediate, and 54% high) treated with RP. Associations between SNPs and BCR were assessed using Cox regression, adjusting for key clinicopathological factors. Functional annotation was performed using HaploReg and FIVEx, while The Cancer Genome Atlas transcriptomic data were analyzed for C2 calcium-dependent domain-containing 4A (<i>C2CD4A</i>) expression. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to explore related biological pathways. <b>Results:</b><i>C2CD4A</i> SNP <i>rs4502156</i> was independently associated with a reduced risk of BCR (hazard ratio = 0.80, <i>p</i> = 0.035). The protective <i>C</i> allele correlated with higher <i>C2CD4A</i> expression. Low <i>C2CD4A</i> expression is associated with advanced pathological stages, higher Gleason scores, and disease progression. GSEA revealed negative enrichment of mitotic and chromatid segregation pathways in high-<i>C2CD4A</i>-expressing tumors, with E2F targets being the most suppressed. GSVA confirmed an inverse correlation between <i>C2CD4A</i> expression and E2F pathway activity, with <i>CDKN2C</i> as a co-expressed functional gene. <b>Conclusions:</b> The T2D-related variant <i>rs4502156</i> in <i>C2CD4A</i> independently predicts a lower risk of BCR, potentially via suppression of the E2F pathway, and may serve as a germline biomarker for postoperative risk stratification.