Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Janky, Rekin's; Binda, Maria; Allemeersch, Joke; Van den broeck, Anke; Govaere, Olivier; Swinnen, Johannes; Roskams, Tania; Aerts, Stein; Topal, Baki
• Is Part Of: BMC cancer. Volume 16:Issue 1(2016)
• Page Start: 1
• Page End: 15
• Publication Date: 2016-12
• Subjects: Pancreatic ductal adenocarcinoma -- Molecular subtypes -- Master regulators -- HNF1A/B; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s12885-016-2540-6
• Languages: English
• ISSNs: 1471-2407

Abstract

Abstract Background 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). Methods 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 usediRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes. Results We confirmed thePDAssign 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. Conclusions 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. Trial registration The study was registered at ClinicalTrials.gov under the numberNCT01116791 (May 3, 2010).