title: Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma.
abstract: Pancreatic cancer is poorly characterized at genetic and non-genetic levels. The current study evaluates in a large cohort of patients the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC).
  
  
  
  We performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 histologically normal pancreatic tissue samples. Cox regression models were used to study the effect on survival of molecular subtypes and 16 clinicopathological prognostic factors. In order to better understand the biology of PDAC we used iRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes.
  
  
  
  We confirmed the PDAssign gene signature as classifier of PDAC in molecular subtypes with prognostic relevance. We found molecular subtypes, but not clinicopathological factors, as independent predictors of survival. Regulatory network analysis predicted that HNF1A/B are among thousand TFs the top enriched master regulators of the genes expressed in the normal pancreatic tissue compared to the PDAC regulatory network. On immunohistochemistry staining of PDAC samples, we observed low expression of HNF1B in well differentiated towards no expression in poorly differentiated PDAC samples. We predicted IRF/STAT, AP-1, and ETS-family members as key transcription factors in gene signatures downstream of mutated KRAS.
  
  
  
  PDAC can be classified in molecular subtypes that independently predict survival. HNF1A/B seem to be good candidates as master regulators of pancreatic differentiation, which at the protein level loses its expression in malignant ductal cells of the pancreas, suggesting its putative role as tumor suppressor in pancreatic cancer.
  
  
  
  The study was registered at ClinicalTrials.gov under the number NCT01116791 (May 3, 2010).
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Herestraat 49, 3000, Leuven, Belgium. rekins.janky@vib.be.
authors: Rekin's
authors: R
authors: Janky
authors: Department of Abdominal Surgical Oncology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors: Maria Mercedes
authors: MM
authors: Binda
authors: Nucleomics Core, Flanders Institute for Biotechnology (VIB), KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors: Joke
authors: J
authors: Allemeersch
authors: Department of Abdominal Surgical Oncology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors: Anke
authors: A
authors: Van den Broeck
authors: Department of Pathology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors: Olivier
authors: O
authors: Govaere
authors: Laboratory of Lipid Metabolism and Cancer, Department of Oncology, LKI-Leuven Cancer Institute, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors: Johannes V
authors: JV
authors: Swinnen
authors: Department of Pathology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors: Tania
authors: T
authors: Roskams
authors: Laboratory of Computational Biology, KU Leuven Center for Human Genetics, Herestraat 49, 3000, Leuven, Belgium. stein.aerts@med.kuleuven.be.
authors: Stein
authors: S
authors: Aerts
authors: Department of Abdominal Surgical Oncology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. baki.topal@med.kuleuven.be.
authors: Baki
authors: B
authors: Topal
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011379:Prognosis; D012044:Regression Analysis; D016019:Survival Analysis
chemical_list: C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta
keywords: HNF1A/B; Master regulators; Molecular subtypes; Pancreatic ductal adenocarcinoma