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. 2020 Feb 14;12(2):451.
doi: 10.3390/cancers12020451.

Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma

Lars M Schiffmann  1 , Heike Loeser  2 , Anne Sophie Jacob  1 , Martin Maus  1 , Hans Fuchs  1 , Yue Zhao  1 , Lars Tharun  2 , Ahlem Essakly  2 , Alexander Iannos Damanakis  1 , Thomas Zander  3 , Reinhard Büttner  2 , Wolfgang Schröder  1 , Christiane Bruns  1 , Alexander Quaas  2 , Florian Gebauer  1
Affiliations

Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma

Lars M Schiffmann et al. Cancers (Basel). .

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.

Keywords: DKK2; EAC; GATA6; response prediction.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Immunohistochemistry of Dickkopf-2 (DKK2) in esophageal adenocarcinoma according to a 4-tier-scoring system; magnification ×400 (A) Negative staining for DKK2 (Score 0); (B) weak staining in tumor cells (Score 1+); (C) weak to moderate staining in most tumor cells (Score 2+); (D) strong staining pattern in >30% of the tumor cells (Score 3+).
Figure 2
Figure 2
RNA-Scope analysis of mi-RNA221 in esophageal adenocarcinomas; magnification ×400 (A) negative tumor cells with less than 1 red signal in 10 tumor cells; (B) mi-RNA221 expression in tumor cells (red signals).
Figure 3
Figure 3
Fluorescence in-situ hybridization (FISH) analysis of GATA6 in arrayed esophageal adenocarcinomas; magnification ×630; Copy Number Variations; GATA6 ≙ green; CEN18 ≙ orange; (A) tumor cells with cluster amplification of green GATA6 signals; (B) tumor cells with normal distribution of GATA6 and CEN18 signals.
Figure 4
Figure 4
Kaplan–Meier survival analysis and survival plots for DKK2 expression and the entire cohort (A), patients after primary surgery without neoadjuvant treatment (B), and patients after neoadjuvant treatment (C).
Figure 4
Figure 4
Kaplan–Meier survival analysis and survival plots for DKK2 expression and the entire cohort (A), patients after primary surgery without neoadjuvant treatment (B), and patients after neoadjuvant treatment (C).
Figure 5
Figure 5
Visualization of the connection of DKK2 and GATA6 on gene level based on TCGA data, analyzed by cBioportal (A). Correlation of gene amplification between DKK2 and GATA6 in esophageal adenocarcinoma (B).
See this image and copyright information in PMC

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