title: Utilization of metabolomics to identify serum biomarkers for hepatocellular carcinoma in patients with liver cirrhosis.
abstract: Characterizing the metabolic changes pertaining to hepatocellular carcinoma (HCC) in patients with liver cirrhosis is believed to contribute towards early detection, treatment, and understanding of the molecular mechanisms of HCC. In this study, we compare metabolite levels in sera of 78 HCC cases with 184 cirrhotic controls by using ultra performance liquid chromatography coupled with a hybrid quadrupole time-of-flight mass spectrometry (UPLC-QTOF MS). Following data preprocessing, the most relevant ions in distinguishing HCC cases from patients with cirrhosis are selected by parametric and non-parametric statistical methods. Putative metabolite identifications for these ions are obtained through mass-based database search. Verification of the identities of selected metabolites is conducted by comparing their MS/MS fragmentation patterns and retention time with those from authentic compounds. Quantitation of these metabolites is performed in a subset of the serum samples (10 HCC and 10 cirrhosis) using isotope dilution by selected reaction monitoring (SRM) on triple quadrupole linear ion trap (QqQLIT) and triple quadrupole (QqQ) mass spectrometers. The results of this analysis confirm that metabolites involved in sphingolipid metabolism and phospholipid catabolism such as sphingosine-1-phosphate (S-1-P) and lysophosphatidylcholine (lysoPC 17:0) are up-regulated in sera of HCC vs. those with liver cirrhosis. Down-regulated metabolites include those involved in bile acid biosynthesis (specifically cholesterol metabolism) such as glycochenodeoxycholic acid 3-sulfate (3-sulfo-GCDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), taurocholic acid (TCA), and taurochenodeoxycholate (TCDCA). These results provide useful insights into HCC biomarker discovery utilizing metabolomics as an efficient and cost-effective platform. Our work shows that metabolomic profiling is a promising tool to identify candidate metabolic biomarkers for early detection of HCC cases in high risk population of cirrhotic patients.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA. hwr@georgetown.edu
authors.forename: Habtom W
authors.initials: HW
authors.lastname: Ressom
authors.forename: Jun Feng
authors.initials: JF
authors.lastname: Xiao
authors.forename: Leepika
authors.initials: L
authors.lastname: Tuli
authors.forename: Rency S
authors.initials: RS
authors.lastname: Varghese
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Tsung-Heng
authors.initials: TH
authors.lastname: Tsai
authors.forename: Mohammad R Nezami
authors.initials: MR
authors.lastname: Ranjbar
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jinlian
authors.initials: J
authors.lastname: Wang
authors.forename: Cristina
authors.initials: C
authors.lastname: Di Poto
authors.forename: Amrita K
authors.initials: AK
authors.lastname: Cheema
authors.forename: Mahlet G
authors.initials: MG
authors.lastname: Tadesse
authors.forename: Radoslav
authors.initials: R
authors.lastname: Goldman
authors.forename: Kirti
authors.initials: K
authors.lastname: Shetty
mesh_terms: D015415:Biomarkers / Q000097:blood*; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000150:complications* / Q000175:diagnosis; D019963:Clinical Chemistry Tests / Q000191:economics; D055088:Early Detection of Cancer / Q000379:methods*; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood* / Q000150:complications*; D008113:Liver Neoplasms / Q000097:blood / Q000175:diagnosis*; D055432:Metabolomics
chemical_list: D015415:Biomarkers