Prognostic value of Dickkopf-1 and ß-catenin expression in advanced gastric cancer

Abstract

Background: Dickkopf-1 (DKK1) is a Wnt/ß-catenin pathway antagonist related to gastric cancer (GC) carcinogenesis. However, the prognostic role of combined DKK1 and ß-catenin expression in advanced GC (AGC) is not clear.

Methods: In total, 158 patients with AGC who underwent gastric resection were enrolled in this study. DKK1 and ß-catenin expression was evaluated in whole tumor sections by immunohistochemistry.

Results: DKK1 expression was high in 73 (46.2%) patients, while ß-catenin expression was positive in 51 (32.3%) patients. The expression of DKK1 was positively correlated with that of ß-catenin (P < 0.001). The combined expression of DKK1 and ß-catenin was significantly associated with high N stage (N2 and N3) (P = 0.042). In addition, patients with high DKK expression demonstrated poorer overall (OS) (P < 0.001) and disease-free survival (DFS) (P = 0.001). However, there were no differences between high DKK1 expression with ß-catenin positivity and high DKK1 expression with ß-catenin negativity (OS, P = 0.379: DFS, P = 0.255). Multivariate analysis revealed that high DKK1 alone or high DKK1 with ß-catenin positivity were independent prognostic factors for both OS (high DKK1: hazard ratio [HR], 2.130; 95% confidence interval [CI]; 1.370-3.312, P = 0.001; high DKK1 with ß-catenin positivity: HR, 2.140; 95% CI, 1.343-3.409: P = 0.001) and DFS (high DKK1: HR, 2.092; 95% CI, 1.180-3.708; P = 0.012; high DKK1 with ß-catenin positivity: HR, 2.357; 95% CI, 1.291-4.306; P = 0.005).

Conclusion: Our results indicate that high DKK1 expression regardless of ß-catenin positivity is a crucial prognostic factor for predicting tumor recurrence and survival in patients with resected AGC.

Keywords: Cut value; Dickkopf-1; Gastric cancer; Prognosis.

Fig. 1

Immunohistochemical staining of DKK1 and β-catenin in normal gastric mucosa. Scant expression of DKK1 (a) and membranous staining (b) of β-catenin were observed

Fig. 2

Expression of DKK1 protein in advanced gastric cancer with N1 and N2 is higher than that in N2 and N3

Fig. 3

Immunohistochemical staining of DKK1 and β-catenin staining in GC. Representative images of GC with high expression of DKK1 (a), low expression of DKK1 (b), positive β-catenin staining (c), and negative β-catenin staining (d)

Fig. 4

Kaplan-Meier survival curves were plotted according to DKK1 and β-catenin protein expression. High DKK1 expression was significantly related to poor OS (a) and DFS (b) in GC patients. Patients with positive β-catenin staining showed shorter OS (c), while DFS (d) was not different significantly between patients with positive and those with negative β-catenin staining. The combination of DKK1 and β-catenin expression was evaluated for its impact on OS (e) and DFS (f)