title: Ubiquitin-proteasome profiling for enhanced detection of hepatocellular carcinoma in patients with chronic liver disease.
abstract: OBJECTIVE
  A reliable test for the detection of hepatocellular carcinoma (HCC) could improve disease management. Recent reports suggested a link between abnormalities in the ubiquitin-proteasome system (UPS) and HCC. We investigated the potential of using UPS markers, along with HCC markers, to differentiate HCC from chronic liver disease (CLD).
  
  
  METHODS
  Sera from 135 HCC and 262 CLD patients were retrospectively analyzed for levels of UPS markers (proteasome, ubiquitin, and proteasome enzymatic activities) and the conventional HCC markers alpha fetoprotein (AFP), AFP-L3, and des-gamma-carboxyprothrombin (DCP). Multivariate logistic regression analysis was used to develop a model for differentiating HCC from CLD. The model was developed using a subset of 98 HCC patients and 104 CLD patients with advanced fibrosis or cirrhosis (Metavir F3-4) and then validated using an independent set (37 HCC and 44 CLD (F3-4)).
  
  
  RESULTS
  A UPS signature model incorporating six markers (trypsin-like, caspase-like, chymotrypsin-like, and normalized chymotrypsin-like activities of proteasomes; AFP; and DCP) accurately differentiated HCC from CLD (area under the curve = 0.938 [95% confidence interval, 0.884-0.991]). When analysis was restricted to patients with tumors ≤ 3 cm, the UPS model exhibited higher sensitivity (83.1% vs 51.8%) and specificity (90.2% vs 83.7%) than the three conventional markers, with good positive predictive values (34.2% vs 15.1%). These results were confirmed in the independent validation set.
  
  
  CONCLUSIONS
  The UPS signature in combination with AFP and DCP provides sensitive and specific differentiation of HCC in patients with CLD. The importance of the UPS in HCC suggests that therapeutic approaches targeting the UPS should be explored.
authors.affiliation: Quest Diagnostics Nichols Institute, San Juan Capistrano, California 92675, USA.
authors.forename: Kevin Z
authors.initials: KZ
authors.lastname: Qu
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Wanlong
authors.initials: W
authors.lastname: Ma
authors.forename: Hairong
authors.initials: H
authors.lastname: Li
authors.forename: Xiuqiang
authors.initials: X
authors.lastname: Wang
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Michelle
authors.initials: M
authors.lastname: Lai
authors.forename: Nezam H
authors.initials: NH
authors.lastname: Afdhal
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D001900:Boston; D002140:California; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000175:diagnosis* / Q000201:enzymology; D002908:Chronic Disease; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007118:Immunoassay; D008103:Liver Cirrhosis / Q000097:blood / Q000175:diagnosis* / Q000201:enzymology; D008113:Liver Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000201:enzymology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D046988:Proteasome Endopeptidase Complex / Q000097:blood*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D025801:Ubiquitin / Q000097:blood*; D000509:alpha-Fetoproteins / Q000032:analysis
chemical_list: C097353:AFP protein, human; D014408:Biomarkers, Tumor; D025801:Ubiquitin; D000509:alpha-Fetoproteins; D046988:Proteasome Endopeptidase Complex