[694] Expression of MDM2, MDM4 and p53 and Association with Outcome in 162 Cases of Gastric Adenocarcinoma.

Jonathan B Rock, Ioannis S Hatzaras, Adrian A Suarez, Xiaoping Zhou, Mark P Bloomston, Wendy L Frankel. The Ohio State University Medical Center, Columbus

Background: Gastric adenocarcinoma (GA) is one of the leading causes of cancer-related death worldwide. Polymorphisms in p53 have been associated with risk for development of GA, and p53 mutations have been identified in a significant proportion of these tumors. MDM2 and MDM4 are critical regulators of p53 protein levels, function and subcellular location. Promoter polymorphisms and mutations of MDM2 and MDM4 can deregulate p53 leading to impaired cell cycle arrest and apoptosis. Novel small molecule inhibitors that disrupt the MDM2-p53 interaction are being studied in some cancers. We evaluated the expression of MDM2, MDM4 and p53 and correlated them with outcome in GA.
Design: Gastric adenocarcinomas with available tissue and clinicopathologic data including patient age, gender, tumor grade and outcome were reviewed. Controls were obtained from uninvolved adjacent stomach in 31 cases. Tissue microarrays with 1 mm cores were constructed, stained with antibodies for MDM2, MDM4 and p53, and graded as strongly positive (2), weakly positive (1) and negative (0). Statistical analysis was performed by Chi-Square, Logistic Regression Analysis for correlation with poor differentiation and Cox proportional hazards analysis for survival.
Results: Mean age was 65.8 years with a male to female ratio 1.2:1. No association was seen between age or gender and poor differentiation. Controls were negative for markers except 4 cases with weak staining for MDM4.

MDM2, MDM4 and p53 Staining Intensity in Tumors
 NegativeWeakStrong
MDM2117 (72%)16 (10%)29 (18%)
MDM474 (46%)66 (40%)22 (14%)
p5368 (42%)34 (21%)60 (37%)


By multivariate analysis, strong expression of MDM4 was correlated to poor tumor differentiation (Odds ratio 4.4; 95% C.I. 1.26, 16.67; P = 0.02). No association was identified between MDM2, MDM4 and p53. Weak expression of MDM2 was associated with shorter survival time (Hazards ratio 2.06; 95% C.I. 1.16, 3.65; P = 0.01). In addition, poor differentiation was associated with shorter survival (Hazards ratio 2.1; 95% C.I. 1.38, 3.20; P = 0.001).
Conclusions: Strong expression of MDM4 correlated with poor differentiation, while weak MDM2 was associated with shorter survival. MDM2 and MDM4 were expressed by many GA (28% and 54%, respectively), emerging as potential targets for small molecule inhibitors currently being investigated in other neoplasms.
Category: Gastrointestinal

Tuesday, March 1, 2011 9:30 AM

Poster Session III # 150, Tuesday Morning

 

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