Correlation of Cks1 and p27kip1 with tumor biologic aggressiveness and survival in gastrointestinal stromal tumor

Abstract

e15549 Background: The biologic behavior of gastrointestinal stromal tumors (GIST) based upon morphologic parameters is unpredictable. Cyclin dependent kinase-1 (Cks1) plays an important role in the ubiquitination and proteolysis of p27kip1, a negative regulator of protein kinase Cdk2/cyclin E and Cdk2/cyclin A. This study was to ascertain whether Cks1 overexpression and p27kip1 downregulation were predictive of biologic aggressiveness and overall survival in GIST. Methods: Tissue microarray was built from 61 patients with GIST. Pathology reports as well as clinical follow-up were retrieved. Sections were stained with antibodies to p27kip1 and Cks1. Staining was scored for quantity of tumor cells (%) and intensity (0, 1+ weak staining, 2+ strong staining), and a score was calculated from the product of intensity and %. Tumors were evaluated for correlation of p27kip1 and Cks1 expression level with overall survival time and tumor risk stratification. Tumor risk stratification was classified into very low risk, low risk, intermediate risk, and high risk, and is reflective of intrinsic biologic aggressiveness. Actuarial survival curves were estimated using Kaplan Meier method. Results: The tumors show a high frequency of Cks1 expression (92%; 1+, n=39; 2+, n=17). The % expression ranged from 0–90% (mean 37%). The p27kip1 positive rate is 85% (1+, n=20; 2+, n=32). The % expression ranged from 0–90% (mean 48%). Overall survival ranged from 0.1–10.7 years. By univariate analysis of overall survival using Cox regression model, increased p27kip1 expression (continuous variable) is significantly correlated with overall survival (p=0.04), but Cks1 expression does not (p=0.84). In a univariate analysis of p27kip1 and Cks1 (continuous variables) with risk stratification of the tumor using F-test, higher tumor grade has significantly higher Cks1 expression values (p=0.0045). Conclusions: Our study shows that with univariate analysis high expression of Cks1 expression is significantly associated with increased intrinsic biologic aggressiveness, while high expression of p27kip1 is associated with increased overall survival. The lack of correlation of Cks1 and p27kip1 suggests additional p27kip1 independent mechanisms might play a role in the oncogenesis of GIST. No significant financial relationships to disclose.