Plasma Metabolomics for Discovery of Early Metabolic Markers of Prostate Cancer Based on Ultra-High-Performance Liquid Chromatography-High Resolution Mass Spectrometry

SIMPLE SUMMARY: Correct identification of subjects at high risk is critical in the prevention and early screening of prostate cancer (PCa). Analysis of metabolites in biofluids has shown to be a promising method to identify novel PCa biomarkers. To identify potential biomarkers of PCa, we conducted metabolic profiling of pre-diagnosis plasma metabolite profiles from a large prospective male cohort (n = 418), which included 146 males who developed PCa during a 13-year follow-up and 272 matched controls to investigate the relationship with long-term PCa risk. We show metabolite profiles discriminate males who subsequently developed PCa during the follow-up from matched controls with a high degree of accuracy (AU-ROC 0.92) and highlight 10 metabolites associated with a high risk of PCa. These results suggest that the dysregulation of amino acids and sphingolipid metabolism is associated with future risk of PCa. ABSTRACT: Background: The prevention and early screening of PCa is highly dependent on the identification of new biomarkers. In this study, we investigated whether plasma metabolic profiles from healthy males provide novel early biomarkers associated with future risk of PCa. Methods: Using the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, we identified plasma samples collected from 146 PCa cases up to 13 years prior to diagnosis and 272 matched controls. Plasma metabolic profiles were characterized using ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Results: Orthogonal partial least squares discriminant analysis (OPLS-DA) discriminated PCa cases from controls, with a median area under the receiver operating characteristic curve (AU-ROC) of 0.92 using a 1000-time repeated random sub-sampling validation. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) identified the top 10 most important metabolites (p < 0.001) discriminating PCa cases from controls. Among them, phosphate, ethyl oleate, eicosadienoic acid were higher in individuals that developed PCa than in the controls during the follow-up. In contrast, 2-hydroxyadenine, sphinganine, L-glutamic acid, serotonin, 7-keto cholesterol, tiglyl carnitine, and sphingosine were lower. Conclusion: Our results support the dysregulation of amino acids and sphingolipid metabolism during the development of PCa. After validation in an independent cohort, these signatures may promote the development of new prevention and screening strategies to identify males at future risk of PCa.