Prognostic significance of cell cycle regulating protein expressions in gastric carcinoma patients receiving adjuvant chemotherapy.

Abstract

4084 Background: Division of a cell is regulated by various cell cycle proteins some of which are known as oncogenes or tumor suppressor genes. Generally, overexpression of G1 phase cyclins and loss of cdk inhibitors are associated with poor prognosis in various carcinomas. Methods: We evaluated expression of Ki-67, cyclin D1, cdk4, p16INK4a, cyclin E and p27Kip1 via immunohistochemical staining in 679 gastric cancer patients who received adjuvant chemotherapy after curative radical gastrectomy. All were eligible patients who had been enrolled for randomized adjuvant chemotherapy clinical trial from 2002 to 2006 in Asan Medical Center. Tissue microarrays were made using two 1.5 mm-tumor cores obtained from paraffin blocks of each case. Results: The expression of cyclin D1 (p = 0.001) and p27Kip1 (p = 0.005) showed positive correlation and p16INK4a (p = 0.033) showed negative correlation with disease free survival in univariate analysis. In multivariate analysis by Cox proportional hazard model, pathologic stage (pTNM, p < 0.001), lymphovascular invasion (p < 0.001), type of gastrectomy (p = 0.011), cyclin D1 (p = 0.009), and p16INK4a expression (p < 0.001) were independent prognostic factors of disease-free survivial. When the cases were grouped according to the cyclin D1 and p16INK4a expression, the cyclin D1 positive and p16INK4anegative group showed the best prognosis and the cyclin D1 negative and p16INK4a positive group showed the worst prognosis. Conclusions: The overexpression of cyclin D1 and loss of p16INK4a is generally considered as poor prognostic factors because cyclin D1 is considered as an oncogene and p16INK4a as a tumor suppressor gene. However, our data suggest that in adjuvant chemotherapy setting, the overexpression of cyclin D1 and loss of p16INK4a are good prognostic factors in gastric carcinoma. No significant financial relationships to disclose.