title: Integrated metabolomic profiling of hepatocellular carcinoma in hepatitis C cirrhosis through GC/MS and UPLC/MS-MS.
abstract: OBJECTIVE
  The metabolic pathway disturbances associated with hepatocellular carcinoma (HCC) remain unsatisfactorily characterized. Determination of the metabolic alterations associated with the presence of HCC can improve our understanding of the pathophysiology of this cancer and may provide opportunities for improved disease monitoring of patients at risk for HCC development. To characterize the global metabolic alterations associated with HCC arising from hepatitis C (HCV)-associated cirrhosis using an integrated non-targeted metabolomics methodology employing both gas chromatography/mass spectrometry (GC/MS) and ultrahigh-performance liquid chromatography/electrospray ionization tandem mass spectrometry (UPLC/MS-MS).
  
  
  METHODS
  The global serum metabolomes of 30 HCC patients, 27 hepatitis C cirrhosis disease controls and 30 healthy volunteers were characterized using a metabolomics approach that combined two metabolomics platforms, GC/MS and UPLC/MS-MS. Random forest, multivariate statistics and receiver operator characteristic analysis were performed to identify the most significantly altered metabolites in HCC patients vs. HCV-cirrhosis controls and which therefore exhibited a close association with the presence of HCC.
  
  
  RESULTS
  Elevated 12-hydroxyeicosatetraenoic acid (12-HETE), 15-HETE, sphingosine, γ-glutamyl oxidative stress-associated metabolites, xanthine, amino acids serine, glycine and aspartate, and acylcarnitines were strongly associated with the presence of HCC. Elevations in bile acids and dicarboxylic acids were highly correlated with cirrhosis.
  
  
  CONCLUSIONS
  Integrated metabolomic profiling through GC/MS and UPLC/MS-MS identified global metabolic disturbances in HCC and HCV-cirrhosis. Aberrant amino acid biosynthesis, cell turnover regulation, reactive oxygen species neutralization and eicosanoid pathways may be hallmarks of HCC. Aberrant dicarboxylic acid metabolism, enhanced bile acid metabolism and elevations in fibrinogen cleavage peptides may be signatures of cirrhosis.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA.
authors.forename: Asem I
authors.initials: AI
authors.lastname: Fitian
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Yiling
authors.initials: Y
authors.lastname: Xu
authors.forename: Miguel
authors.initials: M
authors.lastname: Ararat
authors.forename: Roniel
authors.initials: R
authors.lastname: Cabrera
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000097:blood; D000596:Amino Acids / Q000097:blood; D001647:Bile Acids and Salts / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000209:etiology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003998:Dicarboxylic Acids / Q000097:blood; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006526:Hepatitis C / Q000097:blood* / Q000150:complications; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D008103:Liver Cirrhosis / Q000097:blood* / Q000209:etiology; D008113:Liver Neoplasms / Q000097:blood* / Q000209:etiology; D055442:Metabolome / Q000502:physiology*; D055432:Metabolomics / Q000379:methods*; D015999:Multivariate Analysis; D012372:ROC Curve; D013110:Sphingosine / Q000097:blood; D053719:Tandem Mass Spectrometry / Q000379:methods; D019820:Xanthine / Q000097:blood
chemical_list: D000596:Amino Acids; D001647:Bile Acids and Salts; D003998:Dicarboxylic Acids; D006893:Hydroxyeicosatetraenoic Acids; D019820:Xanthine; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D013110:Sphingosine
keywords: Cirrhosis; HCC; Metabolomics; liquid chromatography/mass spectrometry; metabolic profiling