RESUMEN
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.
RESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with an overall 5-year survival rate of just 5%. A better understanding of the carcinogenesis processes and the mechanisms of the progression of PDAC is mandatory. Fifty-two PDAC patients treated with surgery and adjuvant therapy, with available primary tumors, normal tissue, preneoplastic lesions (PanIN), and/or lymph node metastases, were selected for the study. Proteins were extracted from small punches and analyzed by LC-MS/MS using data-independent acquisition. Proteomics data were analyzed using probabilistic graphical models, allowing functional characterization. Comparisons between groups were made using linear mixed models. Three proteomic tumor subtypes were defined. T1 (32% of patients) was related to adhesion, T2 (34%) had metabolic features, and T3 (34%) presented high splicing and nucleoplasm activity. These proteomics subtypes were validated in the PDAC TCGA cohort. Relevant biological processes related to carcinogenesis and tumor progression were studied in each subtype. Carcinogenesis in the T1 subtype seems to be related to an increase of adhesion and complement activation node activity, whereas tumor progression seems to be related to nucleoplasm and translation nodes. Regarding the T2 subtype, it seems that metabolism and, especially, mitochondria act as the motor of cancer development. T3 analyses point out that nucleoplasm, mitochondria and metabolism, and extracellular matrix nodes could be involved in T3 tumor carcinogenesis. The identified processes were different among proteomics subtypes, suggesting that the molecular motor of the disease is different in each subtype. These differences can have implications for the development of future tailored therapeutic approaches for each PDAC proteomics subtype.
