Abstract
Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in United States men. Controversy continues over the effectiveness of prostate-specific antigen (PSA) for distinguishing aggressive from indolent PCa. There is a critical need for more specific and sensitive biomarkers to detect and distinguish low- versus high-risk PCa cases. Discovery metabolomics were performed utilizing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) on plasma samples from 159 men with treatment naïve prostate cancer participating in the North Carolina-Louisiana PCa Project to determine if there were metabolites associated with aggressive PCa. Thirty-five identifiable plasma small molecules were associated with PCa aggressiveness, 15 of which were sphingolipids; nine common molecules were present in both African-American and European-American men. The molecules most associated with PCa aggressiveness were glycosphingolipids; levels of trihexosylceramide and tetrahexosylceramide were most closely associated with high-aggressive PCa. The Cancer Genome Atlas was queried to determine gene alterations within glycosphingolipid metabolism that are associated with PCa and other cancers. Genes that encode enzymes associated with the metabolism of glycosphingolipids were altered in 12% of PCa and >30% of lung, uterine, and ovarian cancers. These data suggest that the identified plasma (glyco)sphingolipids should be further validated for their association with aggressive PCa, suggesting that specific sphingolipids may be included in a diagnostic signature for PCa.
Highlights
Prostate cancer (PCa) is the most diagnosed cancer in men, accounting for over 350,000 deaths worldwide in 2018 [1,2,3]
Discovery metabolomic analyses were performed on plasma samples from 159 men with PCa (Table 1) with similar ages and severity distributions to determine if there was a common set of lipids associated with PCa aggressiveness
Fifteen of the molecular species most associated with PCa aggressiveness were sphingolipids, including the top five by significance (Table S1)
Summary
Prostate cancer (PCa) is the most diagnosed cancer in men, accounting for over 350,000 deaths worldwide in 2018 [1,2,3]. Prostate cancer is still subject to substantial overdiagnosis and screening tests are needed that more accurately identify men with aggressive cancer [4]. Recent studies comparing PSA screened men to those without screening revealed relatively small differences in PCa mortality [5,6,7]. Recent studies have suggested altered sphingolipid levels, glycosphingolipids and their metabolic enzymes, may play critical roles in initiation and malignant transformation of numerous cancers [17]. Our data identify specific glycosphingolipid species to be highly associated with aggressive PCa, suggesting that further analysis of sphingolipids may help identify a novel diagnostic for PCa and play a role in determining PCa aggressiveness in African- and European-American men. Additional details about the study methods and design were published [20]
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