Decreased expression of the GATA3 gene is associated with poor prognosis in primary gastric adenocarcinoma

Abstract

Background: GATA binding protein 3 (GATA3) was recently proposed to function as a tumor suppressor gene in some types of human cancer. This study aims to investigate GATA3 expression and its prognostic significance in primary gastric adenocarcinoma.

Methodology/principal findings: Using real-time quantitative PCR (RT-qPCR) and immunohistochemical staining methods, GATA3 expression was analyzed in tissue samples from a consecutive series of 402 gastric adenocarcinoma patients who underwent resections between 2003 and 2006. The relationship between GATA3 expression, clinicopathological factors, and patient survival was investigated. The expression status of GATA3 was shown to be clearly reduced in the tumor tissue samples compared with that in the matched adjacent non-tumor tissue samples by RT-qPCR (P = 0.0014). Immunohistochemistry analysis indicated that GATA3 expression was significantly decreased in 225 of the 402 (56%) gastric adenocarcinoma cases. Reduced GATA3 expression was also observed in patients with large tumors (P = 0.017), signet ring cell carcinoma or mucinous carcinoma (P = 0.005) and tumors with lymphatic or venous invasion (P = 0.040). Additionally, reduced expression of GATA3 was more commonly observed in tumors that were staged as T4a/b (P<0.001), N3 (P<0.001), or M1 (P<0.001). Kaplan-Meier survival curves revealed that reduced expression of GATA3 was associated with poor prognosis in gastric adenocarcinoma patients (P<0.001). Multivariate Cox analysis identified GATA3 expression as an independent prognostic factor for overall survival (HR = 5.375, 95% CI = 3.647-7.921, P<0.001). To investigate the predictive ability of the models with and without containing GATA3 gene expression, Harrell's c-index was calculated as a measure of predictive accuracy of survival outcome. The c-index values revealed that model containing GATA3 expression (c-index = 0.897) had superior discrimination ability to the model without containg it (c-index = 0.811).

Conclusions/significance: Our data suggest that GATA3 plays an important role in tumor progression and that reduced GATA3 expression independently predicts an unfavorable prognosis in primary gastric adenocarcinoma patients.

Figure 1. Decreased mRNA expression of GATA3 in gastric cancer tissues as assessed by real time quantitative PCR (n = 38, P = 0.0014).

T = Tumor, N = Normal.

Figure 2. GATA3 protein expression in gastric cancer surgical specimens shown by immunohistochemistry.

(A) Strong GATA3 staining (+++) was observed in noncancerous gastric mucosa. (B) GATA3 staining (++) in well differentiated gastric cancer. (C) GATA3 staining (+) in poorly differentiated gastric cancer. (D). Negative GATA3 staining (−) in mucinous carcinoma.

Figure 3. Kaplan-Meier survival curves of gastric cancer patients (n = 402) after gastrectomy.

The survival rate of the patients in the GATA3-low group (n = 225) was significantly lower than that of the patients in the GATA3-high group (n = 177) (log-rank test, P<0.001).