Methylation of p16 CpG Island Associated with Malignant Progression of Oral Epithelial Dysplasia: A Prospective Cohort Study

Abstract

Purpose: Inactivation of p16 gene by CpG methylation is a frequent event in oral epithelial dysplasia. To investigate the predictive value of p16 methylation on malignant potential in oral epithelial dysplasia, we carried out the prospective cohort study. Experimental Design: One hundred one patients with histologically confirmed mild or moderate oral epithelial dysplasia were included in the present cohort study. p16 Methylation status of the oral epithelial dysplasia lesions from 93 cases was obtained by methylation-specific PCR. Progression of the oral epithelial dysplasia lesions was examined in 78 cases histologically during a 45.8 months follow-up period. The association between p16 methylation and progression of oral epithelial dysplasia was analyzed.Results: Of the 93 enrolled cases, 15 cases were lost during the follow-up because of changes of contact information, with a compliance of 83.9%. p16 Methylation was detectable in oral epithelial dysplasia lesions from 32 (41.0%) of 78 enrolled patients. Oral epithelial dysplasia-related squamous cell carcinomas were observed in 22 patients (28.2%) during the follow-up. Rate of progression to oral cancer in patients with the p16-methylated oral epithelial dysplasia was significantly higher than that with the p16-unmethylated oral epithelial dysplasia (43.8% versus 17.4%; adjusted odds ratio, 3.7; P = 0.013), especially for patients at the baseline age of ≥60 years (adjusted odds ratio, 12.0; P = 0.003) and patients with moderate oral epithelial dysplasia (adjusted odds ratio, 15.6; P = 0.022). The overall sensitivity and specificity of prediction of malignant transformation of oral epithelial dysplasia by p16 methylation were 63.6% and 67.9%, respectively. Conclusion: p16 Methylation was correlated with malignant transformation of oral epithelial dysplasia and is a potential biomarker for prediction of prognosis of mild or moderate oral epithelial dysplasia. (Clin Cancer Res 2009;15(16):5178-83)

Differentiation and adaptation epigenetic networks: Translational research in gastric carcinogenesis

“…Epithelial dysplasia is the main precancerous lesion in many organs in the body. We have proven that methylation of p16, the G1→S conversion checkpoint gene in the cell cycle, is a powerful biomarker for predicting malignant transformation of epithelial dysplasia [5,6]. This has been consistently confirmed by a number of independent studies in different countries [7][8][9].…”

Analysis of p16_{<i>CDKN2A</i>} Methylation and HPV-16 Infection in Oral Mucosal Dysplasia

“…Variables Associated with ED A large number of studies have attempted to identify biological markers associated with oral carcinogenesis [6,9,24,25,30,36,37] . In this field, molecular biology has emerged as an important tool for identifying groups of people susceptible to particular diseases [6,30,33,34,38,39] .…”

“…In the current study, we demonstrated that ED was associated with p16 CDKN2A methylation. A recent study suggested that p16 CDKN2A methylation is associated with oral carcinogenesis [36,45] . Moreover, evidence suggests that p16 CDKN2A methylation may serve as a useful molecular marker for predicting local recurrence in tongue carcinoma [46] .…”

The p16-Specific Reactivation and Inhibition of Cell Migration Through Demethylation of CpG Islands by Engineered Transcription Factors

“…Inactivation of p16 (CDKN2A) by CpG methylation is one of the most frequent events in the development of many cancers (Herman et al, 1995;Sun et al, 2004;Jin et al, 2009). Epithelial precancerous lesions containing methylated p16 have a much higher risk of malignant transformation than the negative ones in follow-up studies (Hall et al, 2008;Cao et al, 2009). Inhibitors of DNA methylation and histone deacylation are recognized as useful cancer therapeutic agents through reactivation of the methylated genes.…”