title: Efficient detection of hepatocellular carcinoma by a hybrid blood test of epigenetic and classical protein markers.
abstract: BACKGROUND
  There are few blood tests for an efficient detection of hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection.
  
  
  METHODS
  The abilities of quantitative analyses of 7 genes hypermethylation in serum DNA, α-fetoprotein (AFP) and prothrombin-induced vitamin K absence II (PIVKA-II), and various combinations to detect HCC were evaluated in a training cohort of 164 HCV-infected patients (108 HCCs; 56 non-HCCs). An optimal hybrid detector, built using data for 2 methylated genes (SPINT2 and SRD5A2), AFP, and PIVKA-II, achieved the most satisfactory ability to detect HCC in the training cohort. We evaluated the ability of the optimal hybrid detector to detect HCC in an independent validation cohort of 258 consecutive HCV-infected patients (112 HCCs; 146 non-HCCs) who were newly enrolled in 4 distinct institutes.
  
  
  RESULTS
  In the validation cohort of 258 patients, accuracy, sensitivity, and specificity of the hybrid detector for detection of HCC were 81.4%, 73.2%, and 87.7%, respectively. Notably, even when detecting HCC ≤ 2 cm in diameter, the hybrid detector maintained markedly high abilities (84.6% accuracy, 72.2% sensitivity, 87.7% specificity). Youden's index (sensitivity+specificity - 1) for HCC ≤ 2cm was 0.60, vastly much superior to the 0.39 for AFP at a cut-off value of 20 ng/ml and the 0.28 for PIVKA-II at a cut-off value of 40 mAU/ml.
  
  
  CONCLUSIONS
  These results show that the optimal hybrid blood detector can detect HCV-related HCC more accurately.
authors.affiliation: Departments of Surgery II Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Iizuka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oka
authors.forename: Isao
authors.initials: I
authors.lastname: Sakaida
authors.forename: Toyoki
authors.initials: T
authors.lastname: Moribe
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Miura
authors.forename: Naoki
authors.initials: N
authors.lastname: Kimura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tamatsukuri
authors.forename: Hideo
authors.initials: H
authors.lastname: Ishitsuka
authors.forename: Koichi
authors.initials: K
authors.lastname: Uchida
authors.forename: Shuji
authors.initials: S
authors.lastname: Terai
authors.forename: Satoyoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Okita
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sakata
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Karino
authors.forename: Joji
authors.initials: J
authors.lastname: Toyota
authors.forename: Eiji
authors.initials: E
authors.lastname: Ando
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ide
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tsunedomi
authors.forename: Masahito
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Michihisa
authors.initials: M
authors.lastname: Iida
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tokuhisa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Takao
authors.initials: T
authors.lastname: Tamesa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujita
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hamamoto
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood*; D001774:Blood Chemical Analysis / Q000379:methods*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006526:Hepatitis C / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D011498:Protein Precursors / Q000097:blood*; D011516:Prothrombin; D015203:Reproducibility of Results; D000509:alpha-Fetoproteins / Q000032:analysis*
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D011498:Protein Precursors; D000509:alpha-Fetoproteins; C008208:acarboxyprothrombin; D011516:Prothrombin