GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma
Authors: de Andrés Mónica P. , Jackson Richard , Pilarsky Christian , Schlitter Anna Melissa , Costello Eithne , Greenhalf William , Ghaneh Paula , Knösel Thomas , Palmer Daniel , Rümmele Petra , Weichert Wilko , Büchler Markus , Hackert Thilo , Neoptolemos John P. , Malats Núria , Martinelli Paola , Real Francisco X. 
Published: August 2021

Objective

GATA6 is a master regulator of pancreatic differentiation and a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression is associated with poor patient outcome.GATA4is the second most expressed GATA factor in the pancreas. The aim was to assess whether, and how, GATA4 contributes to PDAC phenotype and to analyze the association of expression with clinical outcome.

Design

We analyzed PDAC transcriptomic data, stratifying cases according toGATA4andGATA6expression, and identified differentially expressed genes and pathways. A multicenter TMA study to assess GATA4 and GATA6 expression in PDAC samples (n=745) from patients undergoing tumour resection was performed using immunohistochemistry with antibodies of validated specificity. GATA4 and GATA6 levels were dichotomized into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models.

Results

Subtype classification using transcriptomic data revealed thatGATA4mRNA is enriched in classical, compared to basal-like tumours. We classified samples in 4 groups as high/low forGATA4andGATA6. Reduced expression ofGATA4did not have a major transcriptional impact. However, concomitant low expression ofGATA4enhanced the transcriptomic effects ofGATA6low expression. Reduced expression of both proteins in tumours was associated with the worst patient survival.GATA4andGATA6expression significantly decreased in metastases and negatively correlated with basal markers.

Conclusions

Our analyses uncover a cooperative interaction betweenGATA4andGATA6to maintain the classical PDAC phenotype and provide compelling clinical rationale for assessing their expression as biomarkers of poor prognosis.

SUMMARY BOX

What is already known about this subject?

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Patients with classical-type PDAC have a better outcome

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Retrospective analyses suggest that classical-type PDAC is more sensitive to 5-FU-based chemotherapy

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GATA6 is a surrogate biomarker of classical tumours and its expression is associated with better survival

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GATA4 and GATA6 have overlapping and unique functions during pancreatic and gastrointestinal development

What are the new findings?

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Tumours displaying only low GATA4 expression have a transcriptomic profile similar to those with preserved expression of both transcription factors

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Combined low expression of GATA4 and GATA6 has the highest transcriptomic impact

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In a large multicenter tissue microarray study, patients with tumours showing low expression of both GATA4 and GATA6 have the worst overall survival

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Low expression of GATA4 and GATA6 is an independent predictor of survival in patients with resectable PDAC

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GATA4 levels are down-regulated in liver metastases and are negatively correlated with basal markers such as KRT5/6, KRT14, and TP63

How might it impact on clinical practice in the foreseeable future?

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The combined assessment of GATA4 and GATA6 expression may improve prognostic stratification of patients with PDAC

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Prospective studies should confirm whether GATA4 and GATA6 expression is also predictive of response to chemotherapy in PDAC patients