Abstract
Dickkopf-2 (DKK2) has been described as Wnt/beta-catenin pathway antagonist and its expression is mediated by micro RNA-221 (miRNA-221). So far, there is only limited data characterizing the role of DKK2 expression in esophageal cancer. A tissue micro array of 192 patients with esophageal adenocarcinoma was analyzed immunohistochemically for DKK2, miRNA-221 expression by RNA scope, and GATA6 amplification by fluorescence in-situ hybridization. The data was correlated with clinical, pathological and molecular data (TP53, HER2, c-myc, GATA6, PIK3CA, and KRAS amplifications). DKK2 expression was detectable in 21.7% and miRNA-221 expression in 33.5% of the patients. We observed no correlation between DKK2 or miRNA-221 expression and clinico-pathological data DKK2 expression was correlated with TP53 mutations and amplification of GATA6. We did not detect a survival difference in dependence of DKK2 for the total cohort, however, in patients without neoadjuvant treatment DKK2 expression correlated with a prolonged survival (median overall-survival 202 vs. 55 months, p = 0.012) which turned opposite in patients that underwent neoadjuvant treatment. High amounts of miRNA-221 were in trend associated with a prolonged overall-survival (p = 0.070). DKK2 as a Wnt antagonist is associated with prolonged survival in patients without neoadjuvant treatment and changes its prognostic value to the contrary in patients after neoadjuvant therapy. The modulatory effects of neoadjuvant treatment in connection with DKK2 expression are not fully understood, but when considering DKK2 as a tumor marker, it is necessary to see it in the context of neoadjuvant therapy.
Highlights
Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies in the gastrointestinal system and overall-survival is hardly improving despite advances in personalized medicine [1].Cancers 2020, 12, 451; doi:10.3390/cancers12020451 www.mdpi.com/journal/cancersCurrently, decisions for or against neoadjuvant treatment regimens are based on clinical parameters obtained during staging routines [2]
It was shown that DKK2 expression is modulated by expression of micro RNA-221 in esophageal cancer [9]
The aim of the present study was to assess the impact of miRNA-221 and DKK2 expression in EAC in a large patient cohort with respect to correlation with clinical parameters and overall-survival, pathological and molecular data
Summary
Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies in the gastrointestinal system and overall-survival is hardly improving despite advances in personalized medicine [1].Cancers 2020, 12, 451; doi:10.3390/cancers12020451 www.mdpi.com/journal/cancersCurrently, decisions for or against neoadjuvant treatment regimens are based on clinical parameters obtained during staging routines [2]. As treatment response is of immense importance for patient’s overall outcome, ongoing studies focus on optimizing multimodal treatment concepts with the aim to improve response rates and thereby overall survival [2,3]. It would be of similar importance to improve our ability to predict response rates to multimodal EAC therapy concepts as of today overall response rates to neoadjuvant treatment are only around 50% and a significant number of patients receive neoadjuvant therapy, which is associated with significant toxicity effects without any benefit for non-responder [4]. The Wnt-pathway latter has been described to be dysregulated in many human diseases including cancer, and its hyperactivation can lead to aberrant cell growth and tumor progression [8]. It has been assumed that DKK2 is a Wnt-antagonist and that, inactivation of DKK2 increases Wnt activity with accelerating tumor progression
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