Frequent Alterations of p16 and p14 in Oral Proliferative Verrucous Leukoplakia

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, p16 and p14 , for homozygous deletion, loss of heterozygosity, and mutation events in 20 PVL cases. Deletion of exon 1B, 1A, or 2 was detected in 40%, 35%, and 0% of patients, respectively. Deletions of exons 1A and 1B 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 IFNa, 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 p16 and p14 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 p16 and p14 occurred in 45% of PVL patients greatly exceeding loss reported in non-PVL dysplastic oral epithelium (15%). In addition, p14 exon 1B 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. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3179–87)