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

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.

The Combination of Individual Herb of Mi-Jian-Chang-Pu Formula Exerts a Synergistic Effect in the Treatment of Ischemic Stroke in Rats

“…In this study, the expression levels of 2-hydroxyadenine, thymine, and 8-hydroxyguanine were downregulated after brain injury, suggesting that nucleotide metabolism balance was related to the occurrence of cerebral ischemia. In addition, the tricarboxylic acid cycle (TCA) is a common metabolic pathway for carbohydrate, fat, and protein metabolism, and 2-hydroxyadenine served as fuel for the TCA, which suggested that the occurrence of IS was related to TCA [ 27 ]. Studies have shown that after brain injury, the expressions of citric acid, fumaric acid, and malic acid were decreased, indicating that the TCA pathway was inhibited [ 28 ].…”

Identification of prediagnostic metabolites associated with prostate cancer risk by untargeted mass spectrometry‐based metabolomics: A case‐control study nested in the Northern Sweden Health and Disease Study

“…11,12 Our previous study nested within the NSHDS 10 and the three EPIC studies 9,11,12 employed a targeted methodology, a kit-based LC-MS 2 assay (Biocrates, Innsbruck, Austria). The three ATBC studies, [5][6][7] one of the SU.VI.MAX studies, 14 the PLCO study, 8 and Cancer Prevention Study-II Nutrition study 16 employed an untargeted MS platform and included only identified metabolites prior to statistical analysis. No previous study employed the (untargeted) analytical methodology used in the present study, that is, LC-high-resolution MS with untargeted data processing using XCMS prior to the feature identification.…”

“…Eleven other prospective studies (six different cohorts) investigating the association of metabolite levels with PCa risk have been published (referred to as “the 11 studies” hereafter) 5‐14,16 . These studies differed in their experimental design and analytical methodologies.…”

“…Attempts have been made to identify prospective associations between prediagnostic concentrations of plasma and serum metabolites and risk of PCa incidence 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 or death due to PCa. 15 , 16 , 17 Glycerophospholipids have been associated with risk of PCa, although to varying degrees.…”

The Integration of Metabolomics with Other Omics: Insights into Understanding Prostate Cancer

“…Metabolites (≤1.5 kD), which include sugars, fatty acids, amino acids, nucleotides, alkaloids, and steroids [1,8] can sometimes be enzymatically transformed into epimetabolites, allowing them to regulate physiological processes [9][10][11]. Because biological matrices are complex with thousands of metabolites in them, the use of analytical methods such as metabolomics allows individual metabolite measurements to be managed [12][13][14][15][16][17][18]. The difference between the two types of metabolomics is that the untargeted approach identifies a single metabolite in a hypothesis-driven manner, while the targeted approach quantifies a metabolite of interest a priori [1,2,19].…”