Liu H, et al. - Whether discrimination of true-total P16 methylation (P16M) from P16 hydroxymethylation (P16H) is needed for predicting cancer development from oral epithelial dysplasias (OEDs) was investigated prospectively in this double blind two-center cohort including patients (n = 265) with mild or moderate OED. They used the 115-bp MethyLight, TET-assisted bisulfite (TAB) methylation-specific PCR (MSP), and TAB-sequencing to analyze total-P16M and P16H. They performed a minimum 24 months follow-up during which OED progression was monitored. They observed a significantly increased cancer progression rate for total-P16M-positive patients vs total-P16M-negative patients. However, similar cancer progression rates were seen between P16H- and true-P16M-positive OEDs. Overall, for determining malignant potential of OEDs, P16H and true-P16M were identified to be comparable biomarkers. In clinical applications, it may be not necessary to distinguish P16H from true-P16M, at least in OED.