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Expression of MAP4K4 Is Associated with Worse Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma

Authors' Affiliations: Departments of ¹ Pathology, ² Gastrointestinal Medical Oncology, and ³ Surgical Oncology, The University of Texas M. D. Anderson Cancer; ⁴ Department of Immunology, Baylor College of Medicine, Houston, Texas and ⁵ Division of Anatomic Pathology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania

Requests for reprints: Huamin Wang, Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Unit 085, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-1846; Fax: 713-563-1848; E-mail: hmwang{at}mdanderson.org.

Purpose: Mitogen-activated protein 4 kinase 4 (MAP4K4) is a serine/threonine kinase and belongs to the mammalian STE20/MAP4K family. Recent studies have shown that MAP4K4 is overexpressed in many types of human cancer and cancer cell lines. MAP4K4 plays an important role in transformation, invasiveness, adhesion, and cell migration. However, the expression of MAP4K4 and its significance in pancreatic ductal adenocarcinoma (PDA) has not been studied.

Experimental Design: We examined the expression of MAP4K4 by immunohistochemistry using tissue microarrays consisting of 66 stage II PDA and their paired benign pancreatic tissue. The staining results were categorized as MAP4K4-H or MAP4K4-L. The results were correlated with clinicopathologic features and patient survival.

Results: MAP4K4 was overexpressed (MAP4K4-H) in 30 of 66 (46%) PDAs and was higher than the paired benign pancreatic tissue samples (19%; P = 0.002). The median overall and recurrence-free survival for patients with MAP4K4-H PDAs were 19.5 and 9.3 months, respectively, compared with 65.2 and 28.8 months for patients with MAP4K4-L tumor (P = 0.02 and 0.0005, log-rank test). MAP4K4 expression was associated with poor overall and recurrence-free survival in univariate analysis (P = 0.02 and 0.001). In multivariate analysis, MAP4K4 expression significantly correlated with overall and recurrence-free survival (P = 0.025 and 0.004) independent of age, tumor size, differentiation, and stage. MAP4K4 expression was also associated with higher frequency of recurrence/metastasis, larger tumor size, and increased number of positive lymph nodes (P < 0.05).

Conclusion: MAP4K4 was overexpressed in about half of PDAs. Overexpression of MAP4K4 was associated with worse prognosis and is a prognostic marker for stage II PDAs.