GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

De Andres MP, Jackson RJ, Felipe I, Zagorac S, Pilarsky C, Schlitter AM, Martinez De Villareal J, Jang GH, Costello E, Gallinger S, Ghaneh P, Greenhalf W, Knoesel T, Palmer DH, Rümmele P, Weichert W, Buechler M, Hackert T, Neoptolemos JP, Notta F, Malats N, Martinelli P, Real FX (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Gut BMJ Publishing Group

DOI: 10.1136/gutjnl-2021-325803

Abstract

Objective GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy. Design We analysed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4 knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models. Results GATA4 messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 had a minor transcriptional impact but low expression of GATA4 enhanced the effects of GATA6 low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. Conclusions GATA4 and GATA6 cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.

Authors with CRIS profile

Christian Pilarsky Professur für Chirurgische Forschung Petra Rümmele Institute of Pathology

Involved external institutions

The University of Liverpool GB United Kingdom (GB) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Ontario Institute for Cancer Research CA Canada (CA) Centro de Investigación Biomédica en Red (CIBER) ES Spain (ES) Medizinische Universität Wien AT Austria (AT) Universitat Pompeu Fabra (UPF) ES Spain (ES) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) ES Spain (ES)

How to cite

APA:

De Andres, M.P., Jackson, R.J., Felipe, I., Zagorac, S., Pilarsky, C., Schlitter, A.M.,... Real, F.X. (2022). GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma. Gut. https://dx.doi.org/10.1136/gutjnl-2021-325803

MLA:

De Andres, Monica P., et al. "GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma." Gut (2022).

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