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Alterations of p16^INK4a and p14^ARF in Patients with Severe Oral Epithelial Dysplasia¹

Division of Environmental Health Sciences, School of Public Health, Comprehensive Cancer Center [L. A. K., T. J. K., H. S., B. C. C., C. M. W.] and The College of Dentistry [S. R. M., M. L.], The Ohio State University, Columbus, Ohio 43210

A number of genetic aberrations have been reported in end-stage squamous cell carcinoma of the head and neck, including p16^INK4a and p14^ARF (INK4a/ARF) inactivation rates of 70–85%. Still, the cell cycle-regulatory genes p16^INK4a and p14^ARF remain poorly understood in oral cavity premalignant lesions. This study evaluated INK4a/ARF locus alterations in 26 patients (28 samples) deemed to be at increased risk for malignant transformation to squamous cell carcinoma due to the diagnosis of severe oral epithelial dysplasia. Microscopically confirmed dysplastic oral epithelium and matching normal tissue were laser capture-microdissected from paraffin sections, DNA was isolated, and molecular techniques were used to evaluate p16^INK4a and p14^ARF gene deletion, mutation, loss of heterozygosity (LOH), and hypermethylation events. Deletion of exon 1ß, 1, or 2 was detected in 3.8%, 11.5%, and 7.7% of patients, respectively. INK4a and ARF mutations were detected in 15.4% and 11.5% of patients with severe dysplasia of the oral epithelium. All identified mutations occurred in the INK4a/ARF conserved exon 2. Allelic imbalance was assessed using three markers previously reported to show high LOH rates in head and neck tumors. LOH was found in 42.1%, 35.0%, and 82.4% of patients for the markers IFN, D9S1748, and D9S171, respectively. Hypermethylation of p16^INK4a and p14^ARF was detected in 57.7% and 3.8% of patients, respectively, using nested, two-stage methylation-specific PCR. The highest rates of p16^INK4a hypermethylation occurred in lesions of the tongue and floor of the mouth. In addition, p16^INK4a hypermethylation was significantly linked to LOH in two or more markers. These data support that INK4a/ARF locus alterations are frequent events preceding the development of oral cancer and that p16^INK4a inactivation occurs to a greater extent in oral dysplasia than does p14^ARF inactivation.

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