Aberrant loss of dickkopf-3 in gastric cancer: can it predict lymph node metastasis preoperatively?

Background: Dickkopf-3 (DKK3) may act as a tumor suppressor as it is down-regulated in various types of cancer. This study assessed the DKK3 protein expression in gastric cancer and its potential value as a prognostic marker.

Methods: DKK3 expression was evaluated by immunohistochemistry in 158 gastric cancer samples from patients who underwent gastrectomy from 2002 to 2008. Clinicopathological parameters and survival data were analyzed.

Results: Loss of DKK3 expression was found in 64 of 158 (40.5%) samples, and it was associated with advanced T stage (p < 0.001), lymph node metastasis (p < 0.001), UICC TNM stage (p < 0.001), tumor location (p = 0.029), lymphovascular invasion (p = 0.035), and perineural invasion (p = 0.032). Patients without DKK3 expression in tumor cells had a significantly worse disease-free and overall survival than those with DKK3 expression (p < 0.001, and p = 0.001, respectively). TNM stage (p = 0.028 and p < 0.001, respectively) and residual tumor (p < 0.001 and p = 0.003, respectively) were independent predictors of disease-free and overall survival. Based on the preoperative clinical stage assessed by computed tomography (CT), loss of DKK3 expression was predominantly associated with worse prognosis in patients with clinically node-negative advanced gastric cancer (AGC). The combination of DKK3 expression status and CT increased the accuracy of CT staging for predicting lymph node involvement from 71.5 to 80.0% in AGC patients.

Conclusion: Loss of DKK3 protein expression was significantly associated with poor survival in patients with gastric cancer and was strongly correlated with the TNM stage. DKK3 might be a potential biomarker of lymph node involvement that can improve the predictive power of CT.