Epidermal Growth Factor Receptor Expression and Gene Copy Number in the Risk of Oral Cancer

Abstract

Leukoplakia is the most common premalignant lesion of the oral cavity. Epidermal growth factor receptor (EGFR) abnormalities are associated with oral tumorigenesis and progression. We hypothesized that EGFR expression and gene copy number changes are predictors of the risk of an oral premalignant lesion (OPL) progressing to oral squamous cell carcinoma (OSCC). A formalin-fixed, paraffin-embedded OPL biopsy specimen was collected from each of 162 patients in a randomized controlled clinical trial. We assessed EGFR expression by immunohistochemistry with two methods: a semiquantitative analysis (145 evaluable specimens) and an automated quantitative analysis (127 evaluable specimens). EGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) in a subset of 49 OPLs with high EGFR expression defined by the semiquantitative analysis. We analyzed EGFR abnormalities for associations with OSCC development. High EGFR expression occurred in 103 (71%) of the 145 OPLs and was associated with a nonsignificantly higher risk of OSCC (P = 0.10). Twenty (41%) of 49 OPLs assessed by FISH had an increased EGFR gene copy number (FISH-positive). Patients with FISH-positive lesions had a significantly higher incidence of OSCC than did patients with FISH-negative (a normal copy number) lesions (P = 0.0007). Of note, 10 of 11 OSCCs that developed at the site of the examined OPL were in the FISH-positive group, leaving only one FISH-negative OPL that did so (P < 0.0001). Our data indicate that an increased EGFR gene copy number is common in and associated with OSCC development in patients with OPLs expressing high EGFR, particularly OSCC developing at the site of a high-expression OPL; they also suggest that EGFR inhibitors may prevent oral cancer in patients with OPLs having an increased EGFR gene copy number. Cancer Prev Res; 3(7); 800-9. ©2010 AACR.

Prognostic Factors, Predictive Markers and Cancer Biology: The Triad for Successful Oral Cancer Chemoprevention

“…In OPML patients enrolled in a retinoid/beta-carotene chemoprevention trial, EGFR protein overexpression and gene copy number gain was associated with increased risk of development of OSCC [33]. Likewise, Poh et al observed that EGFR gene copy number gain occurred more frequently in lesions that subsequently progressed to cancer versus not [35].…”

“…These include (but are not limited to) podoplainin [26], deltaNp63 [17], cyclin D1 genotypes [27], specific mRNA expression [28] and DNA methylation [29] profiles, miRNA-31 [30], human telomerase RNA component (hTERC) gene copy number [31], ABCG2 and BMI-1 expression [32], and EGFR protein, mRNA expression and gene copy number gains [33]. Most of these studies, however, consisted of retrospective analyses, including varying (but often limited) number of specimens, without validation on i ndependent datasets.…”

A Literature Analysis of the Risk Factors for Oral Cancer

“…Increased or aberrant expression of the EGFR or its ligands may lead to many processes important for tumor growth, including cell proliferation, survival, angiogenesis, invasion, and metastasis (Janmaat & Giaccone, 2003). A pervious study investigating EGFR gene in oral premalignant lesion specimens found that increased EGFR gene copy number was associated with higher risk of oral cancer (Taoudi Benchekroun et al, 2010). Other studies found significant increases in EGFR copy number and EGFR immuno-reactivity in oral squamous cell carcinoma patients when compared with long-term betel quid chewers, or compared with matched adjacent oral mucosa (Chiang et al, 2008).…”

Immunological and classical subtypes of oral premalignant lesions

“…Some biomarkers of risk of malignant transformation, such as loss of heterozygosity (LOH), 6–8 and epithelial growth factor receptor ( EGFR ) gene copy number gain, 9 have been identified and validated in OPL. Retrospective and prospective studies completed initially by our group 6 and subsequently by others 7,8 demonstrate that LOH profiles (primarily at 3p14 and/or 9p21) in OPL are the most robust marker of cancer risk in this setting.…”