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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

BMC Cancer 1/2018

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

Zeitschrift:
BMC Cancer > Ausgabe 1/2018
Autoren:
Hongwei Liu, Zhaojun Liu, Xue-wei Liu, Si Xu, Lei Wang, Yang Liu, Jing Zhou, Liankun Gu, Yan Gao, Xiao-yong Liu, Huidong Shi, Zheng Sun, Dajun Deng
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12885-018-4787-6) contains supplementary material, which is available to authorized users.
Hongwei Liu, Zhaojun Liu and Xue-wei Liu contributed equally to this work.

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).
Zusatzmaterial
Additional file 1: Figure S1. Characterization of the true methylation and hydroxymethylation states of CpG sites in the M.sssI-methylated and 5hmC-containing λ-DNA controls (5mC-Ctrl and 5hmC-Ctrl). Bisulfite-modified DNA templates were used to discriminate 5mC or 5hmC from unmethylated cytosine. TAB-modified DNA templates were used to discriminate 5hmC from 5mC or unmethylated cytosine. The CpG sites within the consensus sequences were listed above the corresponding clone sequences. The number of 5hmC or 5mC sites within each clone was also listed on the left side. These control DNA was added into test samples to monitor the conversion status of 5mC, 5hmC, and unmethylated-cytosine in genomic DNA by bisulfite and TAB treatments. (TIF 197 kb)
12885_2018_4787_MOESM1_ESM.tif
Literatur
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