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

Abstract

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.

Overexpression of a Chromatin Remodeling Factor, RSF-1/HBXAP, Correlates with Aggressive Oral Squamous Cell Carcinoma

“…For example, using a genome-wide analysis of DNA copy number changes, we have previously demonstrated that amplification at the ch7p11.2 locus, which harbors epidermal growth factor receptor (EGFR), was the most common DNA copy number alteration in OSCC tissues. 19 Up-regulation of other known oncogenes, such as CCND1 and FGFR genes, was also frequently found in OSCC. 19,22,23 In this study, we demonstrate that a chromatin remodeling factor, RSF-1, may be involved in tumor progression, and may confer disease aggressiveness in OSCC.…”

“…19 Up-regulation of other known oncogenes, such as CCND1 and FGFR genes, was also frequently found in OSCC. 19,22,23 In this study, we demonstrate that a chromatin remodeling factor, RSF-1, may be involved in tumor progression, and may confer disease aggressiveness in OSCC. Moreover, RSF-1 knockdown experiments showed that RSF-1 expression was essential for tumor cell growth and survival in RSF-1-overexpressing OSCC cells.…”

“…Multivariate analysis has shown that RSF-1 overexpression is an independent marker for a worse overall survival in OSCC patients. Currently, overexpression of transforming growth factor-␣ and EGFR in OSCC has been reported to have a strong prognostic value, 19,24 suggesting that RSF-1 immunoreactivity may serve as another OSCC biomarker for clinical outcome prediction. It would be of great interest to determine whether analysis of expression of the combination of RSF-1, transforming growth factor-␣, and EGFR would further improve outcome prediction.…”

“…DNA content of RSF1 gene in each sample was then normalized to that of LINE-1, as previously described. 19 …”

Lentiviral short hairpin RNA screen of human kinases and phosphatases to identify potential biomarkers in oral squamous cancer cells

“…For example, epidermal growth factor receptor (EGFR) has been identified to be amplified in 31% of OSCC patients and correlates with poor clinical outcome. Targeting of EGFR with either a monoclonal antibody against EGFR or a small-molecule EGFR tyrosine kinase inhibitor has been successfully utilized for therapeutic purposes (16,17). Currently, it is believed that personalized treatment is the major cancer therapy strategy in the future.…”