Faculty Collaboration Database

Frequent alterations of p16INK4a and p14ARF in oral proliferative verrucous leukoplakia. Cancer Epidemiol Biomarkers Prev 2008 Nov;17(11):3179-87

Date

11/08/2008

Pubmed ID

18990760

DOI

10.1158/1055-9965.EPI-08-0574

Scopus ID

2-s2.0-55849125827 (requires institutional sign-in at Scopus site)   52 Citations

Abstract

Proliferative verrucous leukoplakia (PVL) represents a rare but highly aggressive form of oral leukoplakia with > 70% progressing to malignancy. Yet, PVL remains biologically and genetically poorly understood. This study evaluated the cell cycle regulatory genes, p16INK4a and p14ARF, for homozygous deletion, loss of heterozygosity, and mutation events in 20 PVL cases. Deletion of exon 1beta, 1alpha, or 2 was detected in 40%, 35%, and 0% of patients, respectively. Deletions of exons 1alpha and 1beta markedly exceed levels reported in non-PVL dysplasias and approximate or exceed levels reported in oral squamous cell carcinomas. Allelic imbalance was assessed for markers reported to be highly polymorphic in squamous cell carcinomas and in oral dysplasias. Loss of heterozygosity was detected in 35.3%, 26.3%, and 45.5% of PVLs for the markers IFNalpha, D9S1748, and D9S171, respectively. INK4a and ARF sequence alterations were detected in 20% and 10% of PVL lesions, accordingly. These data show, for the first time, that both p16INK4a and p14ARF aberrations are common in oral verrucous leukoplakia; however, the mode and incidence of inactivation events differ considerably from those reported in non-PVL oral premalignancy. Specifically, concomitant loss of p16INK4a and p14ARF occurred in 45% of PVL patients greatly exceeding loss reported in non-PVL dysplastic oral epithelium (15%). In addition, p14ARF exon 1beta deletions were highly elevated in PVLs compared with non-PVL dysplasias. These data illustrate that molecular alterations, even within a specific genetic region, are associated with distinct histologic types of oral premalignancy, which may affect disease progression, treatment strategies, and ultimately patient prognosis.

Author List

Kresty LA, Mallery SR, Knobloch TJ, Li J, Lloyd M, Casto BC, Weghorst CM

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

Adult
Aged
Aged, 80 and over
Alleles
Biopsy
Carcinoma, Squamous Cell
Chi-Square Distribution
Chromosomes, Human, Pair 9
Cyclin-Dependent Kinase Inhibitor p16
Exons
Female
Gene Deletion
Humans
Immunoenzyme Techniques
Leukoplakia, Oral
Loss of Heterozygosity
Male
Middle Aged
Mutation
Polymerase Chain Reaction
Precancerous Conditions
Tumor Suppressor Protein p14ARF