Abstract
Simple SummaryMolecular signatures predictive of recurrence-free survival (RFS) and castration resistance are critical for treatment decision-making in prostate cancer (PCa), but the robustness of current signatures is limited. This study aims to identify castration-resistant PCa (CRPC)-associated genes and develop robust RFS and CRPC signatures. Among 287 genes differentially expressed between localized CRPC and hormone-sensitive PCa (HSPC) samples, 6 genes constituted a signature (CRPC-derived prognosis signature, CRPCPS) that predicted RFS. Moreover, a 3-gene panel derived from the 6 CRPCPS genes was capable of distinguishing CRPC from HSPC. The CRPCPS predicted RFS in 5/9 cohorts in the multivariate analysis and maintained prognostic in patients stratified by tumor stage, Gleason score, and lymph node metastasis status. It also predicted overall survival and metastasis-free survival. Notably, the signature was validated in another six independent cohorts. These findings suggest that these two signatures could be robust tools for predicting RFS and CRPC in clinical practice.Molecular signatures predictive of recurrence-free survival (RFS) and castration resistance are critical for treatment decision-making in prostate cancer (PCa), but the robustness of current signatures is limited. Here, we applied the Robust Rank Aggregation (RRA) method to PCa transcriptome profiles and identified 287 genes differentially expressed between localized castration-resistant PCa (CRPC) and hormone-sensitive PCa (HSPC). Least absolute shrinkage and selection operator (LASSO) and stepwise Cox regression analyses of the 287 genes developed a 6-gene signature predictive of RFS in PCa. This signature included NPEPL1, VWF, LMO7, ALDH2, NUAK1, and TPT1, and was named CRPC-derived prognosis signature (CRPCPS). Interestingly, three of these 6 genes constituted another signature capable of distinguishing CRPC from HSPC. The CRPCPS predicted RFS in 5/9 cohorts in the multivariate analysis and remained valid in patients stratified by tumor stage, Gleason score, and lymph node status. The signature also predicted overall survival and metastasis-free survival. The signature’s robustness was demonstrated by the C-index (0.55–0.74) and the calibration plot in all nine cohorts and the 3-, 5-, and 8-year area under the receiver operating characteristic curve (0.67–0.77) in three cohorts. The nomogram analyses demonstrated CRPCPS’ clinical applicability. The CRPCPS thus appears useful for RFS prediction in PCa.
Highlights
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies in men worldwide [1]
The criteria for selecting these datasets included: (1) Gene expression data must be available for both castrationresistant PCa (CRPC) and hormone-sensitive PCa (HSPC) tumors, (2) both CRPCs and HSPC tumors must be derived from the primary site, and (3) at least 5000 genes must be included when the microarray platform is used for expression profiling
Using the “limma” R package, we normalized expression data from datasets GSE6811, GSE2443, GSE28680, and GSE70768, and identified 2588, 1331, 2221, and 10,786 differentially expressed genes (DEGs) between localized CRPC and HSPC tumors respectively, with a cut-off of p < 0.05 (Figure 2a). Integration of these DEGs by the Rank Aggregation (RRA) method resulted in 287 DEGs (|log2FC| ≥ 0.5, p < 0.05), 93 of which were upregulated and 194 downregulated in CRPCs (Table S2)
Summary
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies in men worldwide [1]. In 2019 alone, an estimated 174,650 new cases of PCa were diagnosed, and 31,620 men died of PCa in the United States [2]. While most prostate cancers are benign, some progress to relapse or metastasize to other organs after initial surgery and radiation therapies, presenting a series of aggressive disease characteristics and killing patients. It is estimated that 17–33% of PCa patients who have received radical prostatectomy will experience a biochemical recurrence, and approximately 30% of individuals develop metastatic disease [3,4,5,6,7,8]. Most ADT-treated patients eventually develop a castrationresistant PCa (CRPC) after 12–24 months of ADT treatment, and the median survival time of CRPC patients is approximately 14 months [11]
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