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Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma
Lars M Schiffmann1, Heike Loeser2, Anne Sophie Jacob1
1Department of General, Visceral and Cancer Surgery, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
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.
Insights
Dickkopf-2 (DKK2) expression in esophageal cancer correlates with TP53 mutations and GATA6 amplification. DKK2 indicates prolonged survival without neoadjuvant treatment, but its prognostic value reverses after therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Dickkopf-2 (DKK2), a Wnt/beta-catenin pathway antagonist, has limited characterization in esophageal cancer.
- Micro RNA-221 (miRNA-221) is known to mediate DKK2 expression.
- Understanding DKK2's role is crucial for esophageal adenocarcinoma prognosis.
Purpose of the Study:
- To investigate the expression of DKK2 and miRNA-221 in esophageal adenocarcinoma.
- To correlate DKK2 and miRNA-221 expression with clinical, pathological, and molecular data.
- To evaluate the prognostic significance of DKK2 expression, particularly in relation to neoadjuvant therapy.
Main Methods:
- Analysis of a tissue microarray from 192 esophageal adenocarcinoma patients.
- Immunohistochemistry for DKK2, RNA scope for miRNA-221, and fluorescence in-situ hybridization for GATA6 amplification.
- Correlation with clinical, pathological, and molecular data including TP53, HER2, c-myc, GATA6, PIK3CA, and KRAS amplifications.
Main Results:
- DKK2 was detected in 21.7% and miRNA-221 in 33.5% of patients.
- DKK2 expression correlated with TP53 mutations and GATA6 amplification, but not with other clinico-pathological data.
- DKK2 expression correlated with prolonged survival in patients without neoadjuvant treatment (202 vs. 55 months), but inversely in those who received neoadjuvant therapy. miRNA-221 showed a trend towards prolonged survival (p=0.070).
Conclusions:
- DKK2 expression is associated with specific molecular alterations (TP53, GATA6) in esophageal adenocarcinoma.
- DKK2 serves as a prognostic marker, with its value dependent on neoadjuvant treatment status.
- The prognostic impact of DKK2 in esophageal cancer is modulated by neoadjuvant therapy, necessitating context-specific interpretation.
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