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Simple Summary  Prostate cancer (PC) is a leading cause of cancer death in men in the developed countries. PC mortality is related to tumor relapse following curative therapy to primary tumors. It is thus essential to effectively assess the recurrence risk for personalized patient management. However, the current assessment capacity remains insufficient. We examined tumors produced in animals and samples derived from more than 1100 patients. A unique set of gene expression was observed following PC progression and a multigene panel consisting of 27 genes (Sig27gene) was constructed. Sig27gene is novel and robustly predicts PC relapse in two independent patient populations ( n  = 492 and  n  = 140) at  p  < 2 × 10 −16 . Sig27gene remains an independent risk factor of PC recurrence after adjusting for multiple clinical features. The novel and robust nature of Sig27gene support its translational potential to evaluate the risk of PC relapse in patients with primary PC.    Abstract  IQGAP1 expression was analyzed in: (1) primary prostate cancer, (2) xenografts produced from LNCaP, DU145, and PC3 cells, (3) tumor of  PTEN −/−   and TRAMP mice, and (4) castration resistant PC (CRPC) produced by LNCaP xenografts and  PTEN −/−   mice. IQGAP1 downregulations occurred in CRPC and advanced PCs. The downregulations were associated with rapid PC recurrence in the TCGA PanCancer ( n  = 492,  p  = 0.01) and MSKCC ( n  = 140,  p  = 4 × 10 −6 ) cohorts. Differentially expressed genes ( n  = 598) relative to IQGAP1 downregulation were identified with enrichment in chemotaxis, cytokine signaling, and others along with reductions in immune responses. A novel 27-gene signature (Sig27gene) was constructed from these DEGs through random division of the TCGA cohort into a Training and Testing population. The panel was validated using an independent MSKCC cohort. Sig27gene robustly predicts PC recurrence at (hazard ratio) HR 2.72 and  p  < 2 × 10 −16  in two independent PC cohorts. The prediction remains significant after adjusting for multiple clinical features. The novel and robust nature of Sig27gene underlie its great translational potential as a prognostic biomarker to predict PC relapse risk in patients with primary PC.

Effective Prediction of Prostate Cancer Recurrence through the IQGAP1 Network