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

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. p16Methylation 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) Leukoplakia is the most common oral precancerous lesion (1). About 8% of oral leukoplakia will progress to oral squamous cell carcinoma because about 17% to 25% of the leukoplakia lesions contain oral epithelial dysplasia (2, 3). Current diagnosis of oral epithelial dysplasia is based primarily on morphologic criteria (4). It is virtually impossible to identify a person with oral epithelial dysplasia at high risk for developing oral cancer on histopathologic grounds alone. A practical biomarker is not presently available for clinical management of oral epithelial dysplasia (5). Inactivation of the p16 (CDKN2A) gene is a frequent event in oral epithelial dysplasia and might play an important role in oral carcinogenesis (6). P16 protein is a cell cycle regulator involved in the inhibition of G1 phase progression (7). Methylation of CpG islands of p16 gene silences its transcription (8). Aberrant inactivation of p16 gene by methylation is an early frequent event in multiple human cancers, including oral squamous cell carcinomas and its precancerous oral epithelial dysplasia lesions (9–13). In nested case-control studies, it was observed that p16 methylation was Authors' Affiliations: Peking University School and Hospital of Stomatology, and Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Aetiology, Peking University School of Oncology, Beijing Cancer Hospital/Institute, Beijing, China Received 3/5/09; revised 4/3/09; accepted 4/16/09; published OnlineFirst 8/11/09. Grant support: National Basic Research Program of China (2005CB 522403) andCapital Program forDevelopmentofHealthSciences (grant 434;D.Deng). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Requests for reprints: Hongwei Liu, Department of Oral Medicine, Peking University School of Stomatology, Beijing 100081, China. E-mail: hongweil@ bjmu.edu.cn or Dajun Deng, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Aetiology, PekingUniversity School of Oncology, Beijing Cancer Hospital/Institute, Beijing, 100142, China. Phone: 8610-88196752; Fax: 8610-88122437; E-mail: dengdajun@ bjmu.edu.cn. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0580 5178 Clin Cancer Res 2009;15(16) August 15, 2009 www.aacrjournals.org Research. on April 14, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 11, 2009; DOI: 10.1158/1078-0432.CCR-09-0580