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Steven C. Cunningham, MD; Farin Kamangar, MD, MPH; Min P. Kim, MD; Sommer Hammoud, BS; Raqeeb Haque, MD; Christine Iacobuzio-Donahue, MD, PhD; Raheela Ashfaq, MD; Scott E. Kern, MD; Anirban Maitra, MBBS; Richard E. Heitmiller, MD; Michael A. Choti, MD; Keith D. Lillemoe, MD; John L. Cameron, MD; Charles J. Yeo, MD; Elizabeth Montgomery, MD; Richard D. Schulick, MD

Arch Surg. 2006;141:1095-1099.

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.

Author Affiliations: Departments of Oncology (Drs Cunningham, Iacobuzio-Donahue, Kern, and Yeo), Pathology (Drs Iacobuzio-Donahue, Maitra, Ashfaq, and Montgomery), and Surgery (Drs Heitmiller, Choti, Lillemoe, Cameron, Yeo, and Schulick); Curriculum in Medicine (Drs Kim and Haque, and Ms Hammoud); and Department of Epidemiology, Bloomberg School of Public Health (Dr Kamangar), The Johns Hopkins University School of Medicine, Baltimore, Md. Dr Cunningham is now with the Department of Surgery, University of Maryland School of Medicine, Baltimore; Dr Kim is now with the Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Mass; Dr Heitmiller is now with the Department of Surgery, Union Memorial Hospital, Baltimore; and Dr Lillemoe is now with the Department of Surgery, Indiana University, Indianapolis.

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MKK4 Status Predicts Survival After Resection of Gastric Adenocarcinoma—Invited Critique
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