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Increased Epidermal Growth Factor Receptor Gene Copy Number Is Associated With Poor Prognosis in Head and Neck Squamous Cell Carcinomas

Christine H. Chung, Kim Ely, Loris McGavran, Marileila Varella-Garcia, Joel Parker, Natalie Parker, Carolyn Jarrett, Jesse Carter, Barbara A. Murphy, James Netterville, Brian B. Burkey, Robert Sinard, Anthony Cmelak, Shawn Levy, Wendell G. Yarbrough, Robbert J.C. Slebos, Fred R. Hirsch

From the Division of Hematology/Oncology, Department of Medicine, Department of Cancer Biology, Department of Pathology, Department of Otolaryngology, Department of Radiation Oncology, Department of Biomedical Informatics, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN; Department of Pathology, Colorado Genetics Laboratory, Department of Medicine, University of Colorado Cancer Center, University of Colorado Health Sciences Center, Aurora, CO; and Constella Health Sciences, Durham, NC

Address reprint requests to Christine H. Chung, MD, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University School of Medicine, 777 Preston Research Building, Nashville, TN 37232-6307; e-mail: Christine.Chung{at}Vanderbilt.edu

Purpose: High epidermal growth factor receptor (EGFR) gene copy number is associated with poor prognosis in lung cancer, but such findings have not been reported for HNSCC. A better understanding of the EGFR pathway may improve the use of EGFR inhibitors in HNSCC.

Patients and Methods: EGFR status was analyzed in 86 tumor samples from 82 HNSCC patients by fluorescent in situ hybridization (FISH) to determine EGFR gene copy number, by polymerase chain reaction and direct sequencing for activating mutations, and by DNA microarray and immunohistochemistry for RNA and protein expression. The results were associated with patient characteristics and clinical end points.

Results: Forty-three (58%) of 75 samples with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH positive). The FISH-positive group did not differ from the FISH-negative group with respect to age, sex, race, tumor grade, subsites and stage, or EGFR expression by analyses of RNA or protein. No activating EGFR mutations were found. However, the FISH-positive group was associated with worse progression-free and overall survival (P < .05 and P < .01, respectively; log-rank test). When microarray data were interrogated using the FISH results as a supervising parameter, ECop (which is known to coamplify with EGFR and regulate nuclear factor-kappa B transcriptional activity) had higher expression in FISH-positive tumors.

Conclusion: High EGFR gene copy number by FISH is frequent in HNSCC and is a poor prognostic indicator. Additional investigation is indicated to determine the biologic significance and implications for EGFR inhibitor therapies in HNSCC.

Supported by Vanderbilt Physician-Scientist Development Award (C.H.C.), the Damon Runyon Clinical Investigator Award (CI-28-05, C.H.C.), the Robert J. Kleberg Jr, and Helen C. Kleberg Foundation (C.H.C. and W.G.Y.), the Barry Baker Laboratory for Head and Neck Oncology (W.G.Y.), and the Vanderbilt-Ingram Cancer Center.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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