This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-3199v1 69/6/2568    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sheu, J. J.-C. Articles by Tsai, F.-J. Search for Related Content PubMed PubMed Citation Articles by Sheu, J. J.-C. Articles by Tsai, F.-J.

Functional Genomic Analysis Identified Epidermal Growth Factor Receptor Activation as the Most Common Genetic Event in Oral Squamous Cell Carcinoma

¹ Graduate Institute of Chinese Medical Science and ² Graduate Institute of Basic Medical Science, China Medical University; ³ Department of Medical Research and ⁴ Department of Otolaryngology, China Medical University Hospital, Taichung, Taiwan; ⁵ Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan; and ⁶ Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: Fuu-Jen Tsai, Human Genetic Center, China Medical University Hospital, 2 Yu-Der Road, Taichung City 40447, Taiwan. Phone: 886-4-22052121, ext. 7080; E-mail: d0704{at}www.cmuh.org.tw or Ie-Ming Shih, Department of Pathology, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB-II, Room 305, Baltimore, MD 21231. Phone: 410-502-7774; Fax: 410-502-4943; E-mail: ishih{at}jhmi.edu.

Key Words: functional genomics • oral squamous cell carcinoma (OSCC) • 7p11.2 amplicon • EGFR amplification/activation

A 250K single-nucleotide polymorphism array was used to study subchromosomal alterations in oral squamous cell carcinoma (OSCC). The most frequent amplification was found at 7p11.2 in 9 of 29 (31%) oral cancer patients. Minimal genomic mapping verified a unique amplicon spanning from 54.6 to 55.3 Mb on chromosome 7, which contains SEC61G and epidermal growth factor receptor (EGFR). Results from fluorescence in situ hybridization, transcriptome, and immunohistochemistry analyses indicated that the expression level of EGFR, but not of SEC61G, was up-regulated and tightly correlated with DNA copy number in 7p11.2 amplified tumors. Among the members of the erbB family, EGFR (HER1) was found to be the most frequently amplified and highly expressed gene in both human and mouse oral tumors (P < 0.01). Genes for downstream effectors of EGFR, including KRAS, mitogen-activated protein kinase 1, and CCND1, were also found amplified or mutated, which resulted in activation of EGFR signaling in 55% of OSCC patients. Head and neck squamous cancer cells with different EGFR expression levels showed differential sensitivity to antitumor effects of AG1478, a potent EGFR inhibitor. AG1478-induced EGFR inactivation significantly suppressed tumor development and progression in a mouse oral cancer model. Our data suggest that EGFR signaling is important in oral cancer development and that anti-EGFR therapy would benefit patients who carry the 7p11.2 amplicon in their tumors. [Cancer Res 2009;69(6):2568–76]