Hypothesis: Lack of expression of the tumor-suppressor gene MKK4 is significantly correlated with poor survival after resection of gastric adenocarcinoma. Design: Retrospective review of medical records after construction and immunolabeling of tissue microarrays for clinical correlation. Setting: The Johns Hopkins Hospital, Baltimore, Md. Patients: Patients operated on because of gastric adenocarcinoma between 1983 and 1995. Main Outcome Measure: Long-term survival and MKK4 status. Results: Primary tumors (N = 124) were scored as 0 (no labeling), 1+ (weak labeling), or 2+ (strong labeling) in 9 (7%), 80 (65%), and 35 (28%) patients, and 5-year survival in these patients was 0%, 21%, and 28%, respectively. Given the small size (7%) of the MKK4-negative group (as expected, given the 5%-10% incidence of genetic loss in carcinomas), a Cox proportional hazards analysis was performed, adjusting for age, sex, and tumor stage. This multivariate analysis revealed a 5-fold increased risk of death (P<.001) in patients whose primary tumors were MKK4-negative. Furthermore, the addition of MKK4 status significantly improved the Cox model, changing log likelihood from -1410 to -369, confirming that MKK4 status was truly the effector of the survival difference and not a bystander. Conclusions: The lack of expression of the tumor-suppressor gene MKK4 in resected gastric adenocarcinoma is robustly associated with poor survival. This finding may provide a useful prognostic tool in patients with gastric adenocarcinoma.
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