Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University School of Stomatology, Beijing, 100081, China.
Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Aetiology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
BMC Cancer. 2018 Sep 24;18(1):918. doi: 10.1186/s12885-018-4787-6.
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.
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.
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.
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.
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 ).
总 P16 甲基化（P16M），包括 P16 羟甲基化（P16H）和真正的 P16M，与口腔上皮异型增生（OED）的恶性转化相关。真正的 P16M 和 P16H 都是致癌作用的早期事件。本研究的目的是前瞻性确定从 OED 中预测癌症发展时，区分真正的 P16M 和 P16H 是否有必要。
招募了 73 名患有轻度或中度 OED 的患者进入双盲的、两中心的队列。使用 115-bp MethyLight、TET 辅助亚硫酸氢盐（TAB）甲基化特异性 PCR（MSP）和 TAB 测序分析总 P16M 和 P16H。总 P16M 阳性且 P16H 阴性的样本被定义为真正的 P16M 阳性。对 OED 进行了至少 24 个月的随访监测。
在 73 例总 P16M 阳性的 OED 中有 23 例检测到 P16H。对 247 名患者中的 247 名患者进行了随访，最终的依从率为 93.2%。在随访期间（中位数为 41.0 个月），观察到 OED 衍生的鳞状细胞癌，发生率为 13.0%（32/247）。与总 P16M 阴性患者相比，总 P16M 阳性患者的癌症进展率显著增加[23.3%比 8.6%；调整后的优势比=2.67（95%CI：1.19-5.99）]。然而，P16H 阳性和真正的 P16M 阳性 OED 之间的癌症进展率相似[26.1%（6/23）比 22.0%（11/50）；比值比=0.80（95%CI：0.22-2.92）]。这些患者的无癌生存率也相似。
P16H 和真正的 P16M 是用于确定 OED 恶性潜能的相似生物标志物。在临床应用中，至少在 OED 中，区分 P16H 和真正的 P16M 可能不是必需的。
本研究在美国国立卫生研究院临床试验方案注册系统中进行了前瞻性注册（试验编号 NCT02967120，可在 https://ClinicalTrials.gov/ct2/show/NCT02967120 获得）。
