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[Cancer Research 66, 8210-8218, August 15, 2006]
© 2006 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Gene Expression Profiles Identify Epithelial-to-Mesenchymal Transition and Activation of Nuclear Factor-{kappa}B Signaling as Characteristics of a High-risk Head and Neck Squamous Cell Carcinoma

Christine H. Chung1,2, Joel S. Parker8, Kim Ely3, Jesse Carter1, Yajun Yi4, Barbara A. Murphy1, K. Kian Ang9, Adel K. El-Naggar10, Adam M. Zanation11, Anthony J. Cmelak5, Shawn Levy6, Robbert J. Slebos2,7 and Wendell G. Yarbrough2,7

1 Division of Hematology/Oncology, Department of Medicine, 2 Department of Cancer Biology, 3 Department of Pathology, 4 Division of Genetic Medicine, 5 Department of Radiation Oncology, 6 Department of Biomedical Informatics, and 7 Department of Otolaryngology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; 8 Constella Health Sciences, Durham, North Carolina; Departments of 9 Radiation Oncology and 10 Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; and 11 Department of Otolaryngology, University of North Carolina, Chapel Hill, North Carolina

Requests for reprints: Christine H. Chung, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN 37232-6307. Phone: 615-322-4967; E-mail: Christine.Chung{at}vanderbilt.edu.

Gene expression signatures generated from DNA microarray analyses have shown promise as predictive biomarkers of clinical outcome. In this study, we determined a high-risk signature for disease recurrence using formalin-fixed head and neck squamous cell carcinoma (HNSCC) tumors and compared the results with an independent data set obtained from fresh frozen tumors. We also showed that genes involved in epithelial-to-mesenchymal transition (EMT) and nuclear factor-{kappa}B (NF-{kappa}B) signaling deregulation are the most prominent molecular characteristics of the high-risk tumors. Gene expression was determined in 40 samples, including 34 formalin-fixed tissues and 6 matched frozen tissues, from 29 HNSCC patients. A 75-gene list predictive of disease recurrence was determined by training on the formalin-fixed tumor data set and tested on data from the independent frozen tumor set from 60 HNSCC patients. The difference in recurrence-free survival (RFS) between the high-risk versus low-risk groups in the training and test sets was statistically significant (P = 0.002 and 0.03, respectively, log-rank test). In addition, the gene expression data was interrogated using Gene Set Enrichment Analysis to determine biological significance. The most significant sets of genes enriched in the high-risk tumors were genes involving EMT, NF-{kappa}B activation, and cell adhesion. In conclusion, global gene expression analysis is feasible using formalin-fixed tissue. The 75-gene list can be used as a prognostic biomarker of recurrence, and our data suggest that the molecular determinants of EMT and NF-{kappa}B activation can be targeted as the novel therapy in the identified high-risk patients. (Cancer Res 2006; 66(16): 8210-8)




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Copyright © 2006 by the American Association for Cancer Research.