title: Prognostic value of hepatocyte nuclear factors 4α and 1α identified by tissue microarray in resectable hepatocellular carcinoma.
abstract: OBJECTIVE
  This study aimed to investigate the prognostic value of expression of hepatocyte nuclear factors (HNFs) involved in hepatic gene transcription in patients undergoing curative resection for hepatocellular carcinoma (HCC).
  
  
  METHODS
  We performed immunohistochemical analyses on microarrays of the tumors and matched adjacent tissue using antibodies against HNF1α, HNF1β, HNF4α, and α-fetoprotein (AFP). We evaluated the prognostic value of biomarker expression using Cox regression and the Kaplan-Meier method in a training cohort of 220 patients and conducted an independent validation in 232 patients. We also determined whether measurement of HNFs improved risk prediction beyond the use of established factors, using net reclassification improvement (NRI).
  
  
  RESULTS
  Post-surgical recurrence and hepatic death were predicted by intratumoral HNF4α underexpression in both cohorts. In the training cohort they were also predicted by peritumoral HNF1α positivity. A pooled cohort analysis showed that these predictors were independently associated with early but not late-phase recurrence, and resultant mortality. Intratumoral expression levels of HNF4α were correlated with those of HNF1α, HNF1β, and AFP (P < 0.05). Similarly, HNF1α expression in peritumoral tissue was correlated with that of other markers (P < 0.05). There was no significant correlation between expression of HNF4α in tumors and HNF1α in peritumoral tissue. Adding combinations of intratumoral HNF4α and peritumoral HNF1α to 2-year recurrence and 5-year mortality models including known clinicopathological prognostic factors significantly improved the NRI indexes (39% and 44%, respectively; P < 0.05).
  
  
  CONCLUSIONS
  Immunohistological activation of intratumoral HNF4α and depletion of peritumoral HNF1α have prognostic significance for delayed recurrence and death after HCC resection.
authors: Department of Gastroenterology, Asan Medical Center, Seoul, Korea.
authors: Ju Hyun
authors: JH
authors: Shim
authors: Hyo Jeong
authors: HJ
authors: Kang
authors: Seungbong
authors: S
authors: Han
authors: Young-Joo
authors: YJ
authors: Lee
authors: Sung-Gyu
authors: SG
authors: Lee
authors: Eunsil
authors: E
authors: Yu
authors: Han Chu
authors: HC
authors: Lee
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D015331:Cohort Studies; D005260:Female; D005544:Forecasting; D006498:Hepatectomy; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000032:analysis*; D051557:Hepatocyte Nuclear Factor 4 / Q000032:analysis*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology; D011379:Prognosis; D016016:Proportional Hazards Models; D012306:Risk; D013997:Time Factors; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4
keywords: hepatic resection; hepatocellular carcinoma; hepatocyte nuclear factor 1α; hepatocyte nuclear factor 4α; recurrence; survival.