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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma

Authors: Rekin’s Janky, Maria Mercedes Binda, Joke Allemeersch, Anke Van den broeck, Olivier Govaere, Johannes V. Swinnen, Tania Roskams, Stein Aerts, Baki Topal

Published in: BMC Cancer | Issue 1/2016

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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 used iRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes.

Results

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.

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 number NCT01116791 (May 3, 2010).
Appendix
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Metadata
Title
Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma
Authors
Rekin’s Janky
Maria Mercedes Binda
Joke Allemeersch
Anke Van den broeck
Olivier Govaere
Johannes V. Swinnen
Tania Roskams
Stein Aerts
Baki Topal
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2540-6

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