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Cyclin D1 Overexpression Is a Critical Event in Gallbladder Carcinogenesis and Independently Predicts Decreased Survival for Patients with Gallbladder Carcinoma¹

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan

ABSTRACT

This study was designed to test the hypothesis that cyclin D1 overexpression is involved in the multistep process of gallbladder carcinogenesis and can be used to predict poor prognosis for patients with gallbladder carcinoma (GBC). Cyclin D1 expression was examined immunohistochemically in a series of specimens, including 8 normal epithelia, 8 benign adenomyoma lesions, 6 precancerous adenomas, and 37 carcinomas of the gallbladder. Four of the 6 (67%) adenomas and 15 of the 37 (41%) adenocarcinomas demonstrated cyclin D1 overexpression (>5% nuclear staining), whereas all normal epithelia and adenomyoma lesions were negative for cyclin D1. Kaplan-Meier curves showed that cyclin D1 overexpression was significantly related to decreased overall survival (P < 0.05) in patients with GBCs. The Cox proportional hazards model identified cyclin D1 overexpression as an independent prognostic marker for death (P = 0.024; risk ratio, 4.2; 95% confidence interval, 1.2–14.7). To test whether cyclin D1 overexpression is a critical event in gallbladder neoplasms, cyclin-dependent kinase inhibitor p27^Kip1 was introduced to ascertain how cyclin D1 affects clinical outcomes. Subsequently, neoplasms were divided into three groups on the basis of the combination of cyclin D1 expression and p27^Kip1 status, which had been determined previously. Group 1 showed no abnormality in either cyclin D1 or p27^Kip1 expression. Group 2 showed aberrant expression of one of the two proteins, whereas group 3 showed concurrent abnormalities in both proteins. Results indicated that overall survival was greatest in group 1, followed by a significant decrease in group 2 and a more precipitous decrease in group 3. In conclusion, cyclin D1 overexpression is an early event in gallbladder carcinogenesis and independently predicts decreased survival for patients with GBC.

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