The Relationship between the Expression of GATA4 and GATA6 with the Clinical Characteristics and Prognosis of Resectable Pancreatic Adenocarcinoma

Abstract

GATA4 and GATA6 are transcription factors involved in the differentiation and development of PDAC. GATA6 expression is related to the classic molecular subtype, while its absence is related to the basal-like molecular subtype. The aim was to determine the clinical utility of IHC determination of GATA4 and GATA6 in a series of patients with resected PDAC. GATA4 and GATA6 expression was studied by IHC in TMA samples of normal tissue, PanIN, tumor tissue and lymph node metastases from a series of 89 patients with resected PDAC. Its relationship with clinicopathologic variables and the outcome was investigated. Seventy-two (81%) tumors were GATA6+ and 37 (42%) were GATA4+. While GATA4 expression was reduced during tumor progression, GATA6 expression remained highly conserved, except in lymph node metastases. All patients with early stages and well-differentiated tumors were GATA6+. The absence of GATA4 expression was related to smoking. Patients with GATA4+ or GATA6+ tumors had significantly lower Ca 19.9 levels. The expression of GATA4 and GATA6 was related to DFS, being more favorable in the GATA4+/GATA6+ group. The determination of the expression of GATA4 and GATA6 by IHC is feasible and provides complementary clinical and prognostic information that can help improve the stratification of patients with PDAC.

High‐resolution and quantitative spatial analysis reveal intra‐ductal phenotypic and functional diversification in pancreatic cancer

“…For pragmatic subtyping in tissue sections, GATA6 protein is the only routinely used staining‐based biomarker, including in clinical trial settings [12]. We observed differences in expression of GATA6 , not only within patients but even up to the level of single pancreatic tumour ducts.…”

“…In contrast to that valuable study, we integrated a systematic and quantitative approach with markers directly informed by the transcriptomic signatures from two of the seminal publications of PDAC transcriptomic subtypes [4,5]. Indeed, while GATA6 as a marker of the classical subtype has been well validated [11,12,31], many studies nowadays use protein markers presumed to reveal the basal-like subtype. We showed that a marker such as deltaNp63/P40 labels only a fraction of basal-like tumour cells.…”

“…Basal-like tumour cells are less differentiated [5] and express genes related to epithelial-to-mesenchymal transition (EMT), hypoxia [9], and chemoresistance [10]. The expression of GATA6a transcription factor whose primary function is epithelial differentiationis increased in classical tumours and represents a prognostically valuable marker to distinguish both subtypes [11,12]. Nevertheless, recent transcriptomic findings from bulk or single-cell studies revealed the coexistence of classical and basallike regions within a single tumour [13] and the presence of an intermediate cell state with co-expression of classical and basal-like features [14].…”

GATA6 identifies an immune-enriched phenotype linked to favorable outcomes in patients with pancreatic cancer undergoing upfront surgery

“…Although retrospective studies have previously highlighted the prognostic value of GATA6 IHC, linking lower GATA6 histoscores to unfavorable survival outcomes in both resected 14 , 17 and advanced PDAC, 18 it is crucial for prospective studies to substantiate these observations. This study, conducted within the confines of an RCT and a rigorously defined clinical framework, adds an extra layer of validation, emphasizing the imperative for continued exploration of GATA6 as a clinically relevant marker.…”

“…IHC offers an appealing alternative due to its cost effectiveness, widespread availability, and potential for seamless integration into routine clinical practice. Retrospective studies have already demonstrated strong associations between GATA6 high histoscores and prolonged survival in treatment-naive patients with resected PDAC 14 , 17 and those with advanced disease. 18 However, these studies underscore the necessity of prospective investigations to validate their findings.…”