Pankreas kanserlerinde epitelyal mezenkimal geçiş ilişkili morfoloji ile GATA-6 ve LOXL2 ekspresyonunun prognostik önemi

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignancies globally and represents an aggressive disease with a poor prognosis, poorly effective treatment options, and a lack of early detection methods. Epithelial-mesenchymal transition (EMT), as shown in studies, significantly influences the biological behavior of pancreatic cancer. EMT is a process where tumor cells differentiate from the parent tumor by transforming into a mesenchymal phenotype through the activation of transcription factors. During EMT, cells acquire different morphological and immunophenotypic characteristics by losing specific epithelial markers (keratin) and gaining mesenchymal markers (vimentin). Additionally, the loss of adhesion observed with the loss of E-cadherin expression in tumor cells, referred to as tumor budding, and the observation of individual cells or small groups of fewer than 5 cells at the infiltrative edge of the tumor, separated from the main tumor mass, are considered indicators of EMT. One of the regulatory mechanisms in the epithelial-mesenchymal transition (EMT) process is the GATA6 transcription factor, and the LOX-like 2 (LOXL2) enzyme. Several studies have shown that LOXL2 reduces E-cadherin expression, which provides cell adhesion, and promotes epithelial-mesenchymal transition (EMT) in various cancers. GATA6 is believed to exhibit low expression in the basal-like subtype of PDAC, known for its poor prognosis and resistance to chemotherapy, distinguishing it from classic PDAC. In this study, we aim to investigate the role of morphological findings, primarily tumor budding in pancreatic adenocarcinomas, which are believed to be associated with EMT, in predicting tumor biological behavior and the relationship between LOXL2 expression, which plays a role in the regulation of EMT, and these morphologies and prognosis. additionally, by exploring EMT-related gene changes in GATA-6 alterations in PDAC using in-silico methods, we aim to shed light on the developmental processes of EMT pathways. In this study, pathological parameters were assessed, and clinical parameters were recorded in tumor tissue sections from 100 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at Dokuz Eylül University Faculty of Medicine, Department of Medical Pathology between 2011 and 2021. Immunohistochemical analysis was performed on Keratin, Vimentin, E-cadherin, and LOXL2 expressions, and their relationship with prognostic factors was investigated. GATA6 copy number changes in PDAC patients were determined from publicly available databases on Cbioportal.org, and associated genes and mRNA expressions were evaluated. Morphological parameters such as tumor budding (TB), TBHG, MF, and necrosis are related to survival and, when evaluated together, reflect EMT-related findings (p <0.001, p <0.001, p <0.001, p < 0.001). The presence of necrosis was found to be an independent negative prognostic factor for both overall survival and disease-free survival (p =0.023, p =0.015). Patients with a high degree of differentiation (log rank, p =0.002), positive surgical margins (log rank, p <0.001), lymphovascular invasion (p =0.037), and loss of E-cadherin (p =0.028) had shorter survival. LOXL2 epithelial and stromal staining did not show an association with survival. The positivity of vimentin and the stromal staining of LOXL2 in the tumor showed a significant correlation with the pT stage. It was observed that positive tumors had lower pT stages (p=0.027, p=0.011). GATA6 copy number changes were observed in 52 (6%) out of 916 patients. 313 genes were associated with copy number increase, of which 4 (ROCK1, RALBP1, LINC00668, GRB2) are involved in EMT-related pathways. In pathway and ontological enrichment analysis conducted in FEGs with a log2 ratio greater than 1, "pancreatic cancer classic and basal subtype" was statistically significant in biological processes as "epithelial layer preservation." The simultaneous evaluation of these four morphologic findings is believed to reflect EMT processes. Necrosis is a negative independent factor and therefore it is important to mention it in pathology reports. This study did not observe an association between LOXL2 and EMT or survival. GATA6 expression is linked to 18q gain and regulates EMT processes through various mRNA expressions and gene alterations.