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A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study.

ABSTRACT: BACKGROUND:Total P16 methylation (P16M), including P16 hydroxymethylation (P16H) and true-P16M, correlates with malignant transformation of oral epithelial dysplasia (OED). Both true-P16M and P16H are early events in carcinogenesis. The aim of this study is to prospectively determine if discrimination of true-P16M from P16H is necessary for prediction of cancer development from OEDs. METHODS:Patients (n?=?265) with mild or moderate OED were recruited into the double blind two-center cohort. Total-P16M and P16H were analyzed using the 115-bp MethyLight, TET-assisted bisulfite (TAB) methylation-specific PCR (MSP), and TAB-sequencing. Total-P16M-positive and P16H-negative samples were defined as true-P16M-positive. Progression of OEDs was monitored for a minimum 24 months follow-up period. RESULTS:P16H was detected in 23 of 73 (31.5%) total-P16M-positive OEDs. Follow-up information was obtained from 247 patients with an ultimate compliance rate of 93.2%. OED-derived squamous cell carcinomas were observed in 13.0% (32/247) patients during follow-up (median, 41.0 months). The cancer progression rate for total-P16M-positive patients was significantly increased when compared to total-P16M-negative patients [23.3% vs 8.6%; adjusted odds ratio?=?2.67 (95% CI: 1.19-5.99)]. However, the cancer progression rates were similar between P16H- and true-P16M-positive OEDs [26.1% (6/23) vs 22.0% (11/50); odds ratio?=?0.80 (95% CI: 0.22-2.92)]. The cancer-free survival was also similar for these patients. CONCLUSION:P16H and true-P16M are similar biomarkers for determining malignant potential of OEDs. Discrimination of P16H from true-P16M, at least in OED, may be not necessary in clinical applications. TRIAL REGISTRATION:This study is registered prospectively in the U.S. National Institutes of Health Clinical Trials Protocol Registration System (trial number NCT02967120, available at https://ClinicalTrials.gov/ct2/show/NCT02967120 ).

SUBMITTER: Liu H

PROVIDER: S-EPMC6154879 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study.

Liu Hongwei H Liu Zhaojun Z Liu Xue-Wei XW Xu Si S Wang Lei L Liu Yang Y Zhou Jing J Gu Liankun L Gao Yan Y Liu Xiao-Yong XY Shi Huidong H Sun Zheng Z Deng Dajun D

BMC cancer 20180924 1

<h4>Background</h4>Total P16 methylation (P16M), including P16 hydroxymethylation (P16H) and true-P16M, correlates with malignant transformation of oral epithelial dysplasia (OED). Both true-P16M and P16H are early events in carcinogenesis. The aim of this study is to prospectively determine if discrimination of true-P16M from P16H is necessary for prediction of cancer development from OEDs.<h4>Methods</h4>Patients (n = 265) with mild or moderate OED were recruited into the double blind two-cent ...[more]

PMID: 30249192

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Project description:Oral epithelial dysplasia (OED) is a precursor state usually preceding oral squamous cell carcinoma (OSCC). Histological grading is the current gold standard for OED prognostication but is subjective and variable with unreliable outcome prediction. We explore if individual OED histological features can be used to develop and evaluate prognostic models for malignant transformation and recurrence prediction. Digitised tissue slides for a cohort of 109 OED cases were reviewed by three expert pathologists, where the prevalence and agreement of architectural and cytological histological features was assessed and association with clinical outcomes analysed using Cox proportional hazards regression and Kaplan-Meier curves. Within the cohort, the most prevalent features were basal cell hyperplasia (72%) and irregular surface keratin (60%), and least common were verrucous surface (26%), loss of epithelial cohesion (30%), lymphocytic band and dyskeratosis (34%). Several features were significant for transformation (p < 0.036) and recurrence (p < 0.015) including bulbous rete pegs, hyperchromatism, loss of epithelial cohesion, loss of stratification, suprabasal mitoses and nuclear pleomorphism. This led us to propose two prognostic scoring systems including a '6-point model' using the six features showing a greater statistical association with transformation and recurrence (bulbous rete pegs, hyperchromatism, loss of epithelial cohesion, loss of stratification, suprabasal mitoses, nuclear pleomorphism) and a 'two-point model' using the two features with highest inter-pathologist agreement (loss of epithelial cohesion and bulbous rete pegs). Both the 'six point' and 'two point' models showed good predictive ability (AUROC ≥ 0.774 for transformation and 0.726 for recurrence) with further improvement when age, gender and histological grade were added. These results demonstrate a correlation between individual OED histological features and prognosis for the first time. The proposed models have the potential to simplify OED grading and aid patient management. Validation on larger multicentre cohorts with prospective analysis is needed to establish their usefulness in clinical practice.

Project description:BackgroundWhile smoking is known to associate with development of multiple diseases, the underlying mechanisms are still poorly understood. Tobacco smoking can modify the chemical integrity of DNA leading to changes in transcriptional activity, partly through an altered epigenetic state. We aimed to investigate the impact of smoking on lung cells collected from bronchoalveolar lavage (BAL).MethodsWe profiled changes in DNA methylation (5mC) and its oxidised form hydroxymethylation (5hmC) using conventional bisulphite (BS) treatment and oxidative bisulphite treatment with Illumina Infinium MethylationEPIC BeadChip, and examined gene expression by RNA-seq in healthy smokers.FindingsWe identified 1667 total 5mC + 5hmC, 1756 5mC and 67 5hmC differentially methylated positions (DMPs) between smokers and non-smokers (FDR-adjusted P <.05, absolute Δβ >0.15). Both 5mC DMPs and to a lesser extent 5mC + 5hmC were predominantly hypomethylated. In contrast, almost all 5hmC DMPs were hypermethylated, supporting the hypothesis that smoking-associated oxidative stress can lead to DNA demethylation, via the established sequential oxidation of which 5hmC is the first step. While we confirmed differential methylation of previously reported smoking-associated 5mC + 5hmC CpGs using former generations of BeadChips in alveolar macrophages, the large majority of identified DMPs, 5mC + 5hmC (1639/1667), 5mC (1738/1756), and 5hmC (67/67), have not been previously reported. Most of these novel smoking-associating sites are specific to the EPIC BeadChip and, interestingly, many of them are associated to FANTOM5 enhancers. Transcriptional changes affecting 633 transcripts were consistent with DNA methylation profiles and converged to alteration of genes involved in migration, signalling and inflammatory response of immune cells.InterpretationCollectively, these findings suggest that tobacco smoke exposure epigenetically modifies BAL cells, possibly involving a continuous active demethylation and subsequent increased activity of inflammatory processes in the lungs. FUND: The study was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Stockholm County Council (ALF), the King Gustav's and Queen Victoria's Freemasons' Foundation, Knut and Alice Wallenberg Foundation, Neuro Sweden, and the Swedish MS foundation.

Dataset Information

A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study.

Publications

A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study.

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