Abnormal Expression of p16INK4a, Cyclin D1, Cyclin-Dependent Kinase 4 and Retinoblastoma Protein in Gastric Carcinomas

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Background and Objectives:The p16 INK4a (p16), cyclin D1, cyclin-dependent kinase (CDK) 4 and retinoblastoma (Rb) genes are components of the Rb pathway that controls the G1-S checkpoint of the cell cycle. The aim of this study was to assess the relationship between their abnormalities and clinicopathological features in gastric carcinomas.Mehtods:Immunohistochemical analysis of the encoded proteins was performed on a series of 158 cases.Results:Loss of p16/Rb protein (pRb) expression and overexpression of cyclin D1/CDK4 were observed in 49%/40% and 37%/37% of gastric carcinomas, respectively. At least 1 of these abnormalities was found in 86% of the cases and a positive correlation was noted between p16 and pRb (P = 0.009). Cyclin D1 (P = 0.042) and CDK4 (P = 0.008) overexpession was inversely associated with lymph node metastasis and depth of invasion, respectively. Loss of pRb expression was more frequently in diffuse type lesions than in the intestinal type (P = 0.022). The patients with p16+/pRb—/cyclin D1—/CDK4— or p16—/pRb+/cyclin D1—/CDK4— tumors demonstrated particularly poor survival. With multivariate survival analysis, only depth of invasion and TNM stage could be proven as independent predictors.Conclusions:The Rb pathway is disrupted in the vast majority of gastric carcinomas. This study also identified specific immunohistochemical marker profiles for prognosis.

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