Usefulness of Amino Acid Profiling in Ovarian Cancer Screening with Special Emphasis on Their Role in Cancerogenesis

Abstract

The aim of this study was to quantitate 42 serum-free amino acids, propose the biochemical explanation of their role in tumor development, and identify new ovarian cancer (OC) biomarkers for potential use in OC screening. The additional value of this work is the schematic presentation of the interrelationship between metabolites which were identified as significant for OC development and progression. The liquid chromatography-tandem mass spectrometry technique using highly-selective multiple reaction monitoring mode and labeled internal standards for each analyzed compound was applied. Performed statistical analyses showed that amino acids are potentially useful as OC biomarkers, especially as variables in multi-marker models. For the distinguishing metabolites the following metabolic pathways involved in cancer growth and development were proposed: histidine metabolism; tryptophan metabolism; arginine biosynthesis; arginine and proline metabolism; and alanine, aspartate and glutamine metabolism. The presented research identifies histidine and citrulline as potential new OC biomarkers. Furthermore, it provides evidence that amino acids are involved in metabolic pathways related to tumor growth and play an important role in cancerogenesis.

Keywords: amino acids; biomarkers; metabolic pathways analysis; ovarian cancer; screening; targeted metabolomics.

Figure 1

Serum concentrations of 5 amino acids that obtained the lowest p-value in the comparison between ovarian cancer (OC) patients and healthy control (HC) group. The optimal cutoff values based on univariate ROC curve analysis are overlaid on the box-plots.

Figure 2

Serum concentrations of 5 amino acids that obtained the lowest p-value in the comparison between ovarian cancer (OC) patients and combined benign ovarian tumor (BOT) and healthy control (HC) group. The optimal cutoff values based on univariate ROC curve analysis are overlaid on the box-plots.

Figure 3

Metabolic pathways proposed to be associated with ovarian cancer (OC) and amino acids altered in OC patients. Red filled arrows represent the concentration of a particular metabolite significantly altered in OC patients (p-value < 0.05), red empty arrows indicate the change in concentration of a particular metabolite in OC patients that was not statistically significant (p-value > 0.05). The crucial intermediates connecting the proposed amino acids and different metabolic pathways are presented in grey. Dotted rectangles represent the endpoint products, pathways or processes. Abbreviations: PRPP—phosphoribosyl pyrophosphate; TCA—tricarboxylic acid.