title: Hepatocyte nuclear factor (HNF) 4α expression distinguishes ampullary cancer subtypes and prognosis after resection.
abstract: OBJECTIVE
  To investigate biological differences and prognostic indicators of different ampullary cancer (AC) subtypes.
  
  
  BACKGROUND
  AC is associated with a favorable prognosis compared with other periampullary carcinomas. Aside from other prognostic factors, the histological origin of AC may determine survival. Specifically, the pancreatobiliary subtype of AC displays worse prognosis compared with the intestinal subtype. However, knowledge of inherent molecular characteristics of different periampullary tumors and their effects on prognosis has been limited.
  
  
  METHODS
  Gene expression profiling was used to screen for differential gene expression between 6 PDAC cases and 12 AC cases. Among others, hepatocyte nuclear factor 4α (HNF4α) mRNA overexpression was observed in AC cases. Nuclear HNF4α protein expression was assessed using tissue microarrays consisting of 99 individual AC samples. The correlation of HNF4α expression with clinicopathological data (n = 99) and survival (n = 84) was assessed.
  
  
  RESULTS
  HNF4α mRNA is 7.61-fold up-regulated in AC compared with that in PDAC. Bioinformatics analyses indicated its key role in dysregulated signaling pathways. Nuclear HNF4α expression correlates with histological subtype, grading, CDX2 positivity, MUC1 negativity and presence of adenomatous components in the carcinoma. The presence of HNF4α is a univariate predictor of survival in AC mean survival (50 months versus 119 months, P = 0.002). Multivariate analysis revealed that HNF4α negativity (HR = 17.95, 95% CI: 2.35-136.93, P = 0.005) and lymph node positivity (HR = 3.33, 95% CI: 1.36-8.18, P = 0.009) are independent negative predictors of survival.
  
  
  CONCLUSIONS
  Immunohistochemical determination of HNF4α expression is an effective tool for distinguishing different AC subtypes. Similarly, HNF4α protein expression is an independent predictor of favorable prognosis in carcinoma of the papilla of Vater and may serve for risk stratification after curative resection.
authors.affiliation: Department of General, Thoracic and Vascular Surgery, University Hospital Dresden, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Ehehalt
authors.forename: Petra
authors.initials: P
authors.lastname: Rümmele
authors.forename: Stephan
authors.initials: S
authors.lastname: Kersting
authors.forename: Corinna
authors.initials: C
authors.lastname: Lang-Schwarz
authors.forename: Felix
authors.initials: F
authors.lastname: Rückert
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Aust
authors.forename: Beatrix
authors.initials: B
authors.lastname: Jahnke
authors.forename: Hans-Detlev
authors.initials: HD
authors.lastname: Saeger
authors.forename: Christian
authors.initials: C
authors.lastname: Pilarsky
authors.forename: Robert
authors.initials: R
authors.lastname: Grützmann
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D000328:Adult; D000368:Aged; D014670:Ampulla of Vater / Q000473:pathology / Q000601:surgery*; D003138:Common Bile Duct Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D056726:Genetic Association Studies; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics; D015996:Survival Rate; D015854:Up-Regulation / Q000235:genetics
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D012333:RNA, Messenger