Frequent Alterations of p16INK4a and p14ARF in Oral Proliferative Verrucous Leukoplakia

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, p16 INK4aand p14 ARF , 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 p16INK4a and p14 ARF 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 p14 ARF occurred in 45% of PVL patients greatly exceeding loss reported in non-PVL dysplastic oral epithelium (15%). In addition, p14 ARF 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)

Salivary and serum interleukin-6 levels in proliferative verrucous leukoplakia

“…Others were not able to detect any definitive relationship with HPV [11,12]. Kresty et al [13] described some genetic changes in these patients, and Kkanrit et al [14] reported a ploidy anomaly. Tobacco does not play a significant role in PVL [2,5,15].…”

The Loss of p16 Expression Worsens the Prognosis of OSCC

“…22,23 The reduction in p16 INK4a expression, in addition to its epigenetic gene silencing, is related to mouth cancer and precancer and it is believed that its inactivation is an early and progressive event as the tumor stage and degree of dysplasia of premalignant lesions advances; at times, this is related to some of the clinical and pathologic parameters or to the expression of other cell-cycle regulatory proteins. 10,[24][25][26][27][28][29][30] In our work we found a gradual reduction in p16 INK4a expression as tumor stages advanced, although without statistically significant differences on quantitative analysis. p16 INK4a is an important marker involved in cellcycle control.…”

No mutations found in exon 2 of gene p16CDKN2A during rat tongue carcinogenesis induced by 4-nitroquinoline-1-oxide

“…In patients with severe oral dysplasia, mutations in the p16CDKN2A gene were infrequent (Kresty et al 2002). In a subsequent study conducted by the same author, deletion of p16CDKN2A exon 2 was not detected (Kresty et al 2008). It is important to stress that 4NQO is an alkylating compound and potent mutagen that requires metabolic activation to be converted to 4-acetoxyaminoquinoline 1-oxide (4HAQO), which reacts with DNA causing damaging effects including single strand breaks, incomplete repair sites and alkali-labile sites.…”