Identification of Metabolism-Associated Prostate Cancer Subtypes and Construction of a Prognostic Risk Model

Background Despite being the second most common tumor in men worldwide, the tumor metabolism-associated mechanisms of prostate cancer (PCa) remain unclear. Herein, this study aimed to investigate the metabolism-associated characteristics of PCa and to develop a metabolism-associated prognostic risk model for patients with PCa. Methods The activity levels of PCa metabolic pathways were determined using mRNA expression profiling of The Cancer Genome Atlas Prostate Adenocarcinoma cohort via single-sample gene set enrichment analysis (ssGSEA). The analyzed samples were divided into three subtypes based on the partitioning around medication algorithm. Tumor characteristics of the subsets were then investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis, differential analysis, Kaplan-Meier survival analysis, and GSEA. Finally, we developed and validated a metabolism-associated prognostic risk model using weighted gene co-expression network analysis, univariate Cox analysis, least absolute shrinkage and selection operator, and multivariate Cox analysis. Other cohorts (GSE54460, GSE70768, genotype-tissue expression, and International Cancer Genome Consortium) were utilized for external validation. Drug sensibility analysis was performed on Genomics of Drug Sensitivity in Cancer and GSE78220 datasets. In total, 1,039 samples and six cell lines were concluded in our work. Results Three metabolism-associated clusters with significantly different characteristics in disease-free survival (DFS), clinical stage, stemness index, tumor microenvironment including stromal and immune cells, DNA mutation (TP53 and SPOP), copy number variation, and microsatellite instability were identified in PCa. Eighty-four of the metabolism-associated module genes were narrowed to a six-gene signature associated with DFS, CACNG4, SLC2A4, EPHX2, CA14, NUDT7, and ADH5 (p <0.05). A risk model was developed, and external validation revealed the strong robustness our risk model possessed in diagnosis and prognosis as well as the association with the cancer feature of drug sensitivity. Conclusions The identified metabolism-associated subtypes reflected the pathogenesis, essential features, and heterogeneity of PCa tumors. Our metabolism-associated risk model may provide clinicians with predictive values for diagnosis, prognosis, and treatment guidance in patients with PCa.