Faculty Collaboration Database

Alterations of p16(INK4a) and p14(ARF) in patients with severe oral epithelial dysplasia. Cancer Res 2002 Sep 15;62(18):5295-300

Date

09/18/2002

Pubmed ID

12234999

Scopus ID

2-s2.0-0037105785 (requires institutional sign-in at Scopus site)   125 Citations

Abstract

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 1beta, 1alpha, 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 IFNalpha, 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.

Author List

Kresty LA, Mallery SR, Knobloch TJ, Song H, Lloyd M, Casto BC, Weghorst CM

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Allelic Imbalance
Biopsy
Chromosomes, Human, Pair 9
Cyclin-Dependent Kinase Inhibitor p16
DNA Methylation
DNA Mutational Analysis
Female
Gene Deletion
Gene Silencing
Humans
Loss of Heterozygosity
Male
Middle Aged
Mouth Mucosa
Mouth Neoplasms
Precancerous Conditions
Tumor Suppressor Protein p14ARF