title: Hepatocyte nuclear factor 1β is a novel prognostic marker independent of the Milan criteria in transplantable hepatocellular carcinoma: a retrospective analysis based on tissue microarrays.
abstract: We retrospectively investigated the prognostic value of hepatocyte nuclear factor 1 (HNF1) proteins in 159 liver transplant patients with hepatocellular carcinoma (HCC), including 36 (22.6%) exceeding the Milan criteria. The expression of alpha-fetoprotein (AFP), HNF1α, and HNF1β was examined with immunohistochemistry on duplicate tissue microarray slides containing HCC tumor explants. The times to recurrence and cancer death were analyzed with a Cox regression model and were compared according to the expression of markers of interest. We compared risk predictions with area under the receiver operator curves (AUROCs) and C statistics. AFP, HNF1α, and HNF1β were positive in 22.6%, 46.5%, and 61.0% of the tumor immunoprofiles, respectively. Although several variables were associated with the times to recurrence and cancer death in univariate Cox analyses, only AFP expression for the time to recurrence and the Milan criteria and HNF1β expression for the times to recurrence and cancer death remained significant after multivariate adjustments. The expression of HNF1β (but not HNF1α) was related to a serum AFP level ≥ 200 ng/mL, microvascular invasion, and AFP expression (P < 0.05 for all). A subgroup analysis showed that in the group meeting the Milan criteria, recurrence and cancer death rates at 10 years in the HNF1β-negative patients were approximately one-tenth of those in the HNF1β-positive patients, but the difference was not significant in the group exceeding the Milan criteria. The addition of HNF1β expression to the Milan criteria increased the C statistics and AUROCs for both recurrence and mortality (P < 0.05 for all). In conclusion, the immunohistological detection of HNF1β predicts recurrence and HCC-specific death after transplantation and provides an additive benefit in comparison with the Milan selection criteria on their own.
authors.affiliation: Department of Gastroenterology (Asan Liver Center), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Shim
authors.forename: Han Chu
authors.initials: HC
authors.lastname: Lee
authors.forename: Seungbong
authors.initials: S
authors.lastname: Han
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kang
authors.forename: Eunsil
authors.initials: E
authors.lastname: Yu
authors.forename: Sung-Gyu
authors.initials: SG
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000401:mortality / Q000556:secondary / Q000601:surgery*; D016009:Chi-Square Distribution; D003661:Decision Support Techniques; D005260:Female; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000032:analysis; D051539:Hepatocyte Nuclear Factor 1-beta / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012372:ROC Curve; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D055815:Young Adult; D000509:alpha-Fetoproteins / Q000032:analysis
chemical_list: C097353:AFP protein, human; D014408:Biomarkers, Tumor; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D000509:alpha-Fetoproteins; D051539:Hepatocyte Nuclear Factor 1-beta