SPAG1 Expression as a Candidate Predictor of Pathological Lymph Node Metastasis in Prostate Cancer: A Transcriptomic Analysis of The Cancer Genome Atlas Prostate Adenocarcinoma Cohort

Background/Objectives: Improved preoperative prediction of nodal metastasis in prostate cancer could refine selection for extended pelvic lymph node dissection, a high-morbidity procedure. Sperm-associated antigen 1 (SPAG1) is a candidate marker of nodal status, but its incremental value beyond clinical staging and the associated transcriptional state remain unevaluated. Methods: In The Cancer Genome Atlas prostate adenocarcinoma (TCGA-PRAD) cohort (497 patients with matched clinical and RNA-sequencing data), we evaluated the association between SPAG1 expression and pathological N stage by logistic regression with 2000-resample bootstrap optimism correction and sensitivity analyses for missing nodal data and batch effects. Hallmark enrichment analysis compared SPAG1 expression extremes (quartile 4 vs. 1) and, separately, N1 versus N0 tumours adjusted for T stage, Gleason grade, and tissue source site; directional concordance was assessed. Results: N1 rates rose across SPAG1 quartiles from 7.6% to 39.0% (per-quartile odds ratio [OR], 1.83; p = 2.55 × 10−5). After adjusting for T stage and Gleason grade, SPAG1 remained an independent predictor (adjusted OR, 2.14; 95% confidence interval [CI], 1.50–3.13; p = 4.8 × 10−5), stable across both sensitivity analyses. Adding SPAG1 improved discrimination (area under the receiver-operating characteristic curve, 0.783 to 0.838; ΔAUC, 0.056; paired DeLong p = 3.03 × 10−5). The SPAG1 transcriptional programme showed cell-cycle, immune–inflammatory, and mTORC1/TGF-β signalling activation with suppressed differentiation and metabolism; all 15 overlapping Hallmark pathways were directionally concordant with the adjusted N1 signature. Conclusions: SPAG1 expression in primary prostate tumours is a candidate predictor of pathological lymph node metastasis with statistically robust incremental discrimination beyond clinical staging. Independent external validation and biopsy-based feasibility studies are required before clinical application.