Prostate Cancer Patients–Negative Biopsy Controls Discrimination by Untargeted Metabolomics Analysis of Urine by LC-QTOF: Upstream Information on Other Omics

Abstract

The existing clinical biomarkers for prostate cancer (PCa) diagnosis are far from ideal (e.g., the prostate specific antigen (PSA) serum level suffers from lack of specificity, providing frequent false positives leading to over-diagnosis). A key step in the search for minimum invasive tests to complement or replace PSA should be supported on the changes experienced by the biochemical pathways in PCa patients as compared to negative biopsy control individuals. In this research a comprehensive global analysis by LC–QTOF was applied to urine from 62 patients with a clinically significant PCa and 42 healthy individuals, both groups confirmed by biopsy. An unpaired t-test (p-value < 0.05) provided 28 significant metabolites tentatively identified in urine, used to develop a partial least squares discriminant analysis (PLS-DA) model characterized by 88.4 and 92.9% of sensitivity and specificity, respectively. Among the 28 significant metabolites 27 were present at lower concentrations in PCa patients than in control individuals, while only one reported higher concentrations in PCa patients. The connection among the biochemical pathways in which they are involved (DNA methylation, epigenetic marks on histones and RNA cap methylation) could explain the concentration changes with PCa and supports, once again, the role of metabolomics in upstream processes.

Metabolomics in the Context of Forensic Omics Biomarkers

“…One other classification of biomarkers is based on the number of compounds forming part of the given biomarker. This classification is characteristic of metabolomics biomarkers, giving place to single metabolite biomarkers and panel metabolite biomarkers [10,11].…”

“…Since then, metabolomics has provided numerous biomarkers in the clinical area in general and in forensics in particular, despite it is hardly taken into account most times. For example, in the characterization of the salivary epigenome, the importance of previous work in dealing with the salivary microbiome, proteome, endocrine analytes, genome, and transcriptome was highlighted [37], but the possible role of metabolomics was ignored, despite its crucial importance in unraveling epigenetic behavior [10]. At present, the importance of metabolomics biomarkers increases at a fast rhythm [38,39], even surpassing wellestablished proteomics biomarkers.…”

Multiple markers for the non-invasive diagnosis and characterisation of prostate cancer

“…Analysis of urine has reported to improve diagnosis (sensitivity 88.4%, specificity 93%) and showed many dysregulated metabolic pathways 293 . Using MetaboAnalyst, upregulation of purine and pyramidine metabolism as well as downregulation of multiple pathways (histidine, arginine, tyrosine, tryptophan, taurine, alanine, aspartate, glutamate) was observed 293 .…”

“…Using MetaboAnalyst, upregulation of purine and pyramidine metabolism as well as downregulation of multiple pathways (histidine, arginine, tyrosine, tryptophan, taurine, alanine, aspartate, glutamate) was observed 293 . Other investigators have observed implicated deranged pathways including the urea and tricarboxylic acid cycle as well as amino acid and purine metabolism in urine samples 294 .…”

“…Profiling of metabolites, or metabolomics, applied to urine has provided biomarker panels reported to significantly improve diagnostic accuracy 293 . Furthermore, local and systemic metabolic disturbances have been suggested, with fatty acid synthesis most commonly implicated 294 .…”