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GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma.
de Andrés, Mónica P; Jackson, Richard J; Felipe, Irene; Zagorac, Sladjana; Pilarsky, Christian; Schlitter, Anna Melissa; Martinez de Villareal, Jaime; Jang, Gun Ho; Costello, Eithne; Gallinger, Steve; Ghaneh, Paula; Greenhalf, William; Knösel, Thomas; Palmer, Daniel H; Ruemmele, Petra; Weichert, Wilko; Buechler, Markus; Hackert, Thilo; Neoptolemos, John P; Notta, Faiyaz; Malats, Núria; Martinelli, Paola; Real, Francisco X.
Afiliação
  • de Andrés MP; Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
  • Jackson RJ; Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
  • Felipe I; Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
  • Zagorac S; CIBERONC, Madrid, Spain.
  • Pilarsky C; Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
  • Schlitter AM; Department of Surgery, Universitätsklinikum Erlangen, Erlangen, Germany.
  • Martinez de Villareal J; Institute of Pathology, School of Medicine, Technische Universitat Munchen, Munchen, Germany.
  • Jang GH; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Costello E; Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
  • Gallinger S; CIBERONC, Madrid, Spain.
  • Ghaneh P; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Greenhalf W; Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
  • Knösel T; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Palmer DH; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
  • Ruemmele P; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University, Toronto, Ontario, Canada.
  • Weichert W; Health Network, Toronto, Ontario, Canada.
  • Buechler M; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada.
  • Hackert T; Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
  • Neoptolemos JP; Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
  • Notta F; Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany.
  • Malats N; Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
  • Martinelli P; Pathologisches Institute, Erlangen University Hospital, Erlangen, Germany.
  • Real FX; Institute of Pathology, School of Medicine, Technische Universitat Munchen, Munchen, Germany.
Gut ; 72(3): 535-548, 2023 03.
Article em En | MEDLINE | ID: mdl-36109153
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Idioma: En Ano de publicação: 2023 Tipo de documento: Article