Comprehensive characterization and evaluation of hepatocellular carcinoma by LC-MS based serum metabolomics

The liver is an active organ in energy metabolism, and hepatocellular carcinomas (HCC) therefore unavoidably induce a series of metabolic alterations in the serum metabolome. In this study, 587 sera from HCC patients, hepatitis B virus (HBV) infected subjects and healthy control subjects were employed to characterize metabolic alterations using a liquid chromatography tandem mass spectrometry-based metabolomics approach. d-Galactose significantly increased whereas undecanoyl-l-carnitine and PE (P-18:0/0:0) decreased in HCC patients when compared with non-HCC controls (HBVs and NCs). These metabolites were finally identified as independent diagnostic factors for HCC discrimination. The combination of discriminative metabolites and alpha-fetoprotein could also significantly improve the diagnostic performance for HCC in terms of the sensitivity, specificity and area under the curve of the receiver operating characteristic curve; these three parameters displayed values of 0.96, 0.92 and 0.98, respectively. Furthermore, network and pathway analyses were conducted to explore the latent relationship among differential metabolites. In the network analysis, metabolites of diverse categories (including amino acids, dipeptides, phospholipids, fatty acids, steroids and acylcarnitines) reflected the correlation between metabolite categories on material and energy conversion in HCC. Meanwhile, metabolites mapped in the pathways for primary bile acid biosynthesis and alanine, aspartate and glutamate metabolism revealed a centrality and significant variances. These results indicated that substantial biochemical perturbations occurred in these pathways in HCC patients. In summary, our study revealed the systematic landscape for metabolic alterations in the serum of HCC patients and provides useful information to clinicians and biologists.