Association between p16 methylation and malignant transformation of gastric dysplasia

目的 山东省临朐县是我国北方胃癌高发区之一,人群中胃黏膜异型增生(dysplasia,DYS)病变所占比例较高.DYS是胃黏膜癌前病变发展的高级阶段,具有显著的恶性转化潜能.本研究探讨p16基因甲基化与DYS病变恶性转化的关系,验证其作为胃癌预警标志物的应用价值.方法 以胃癌高发现场长期胃镜随访队列为基础,对101例来自山东省临朐县胃癌高发区且随访至2015-12-31的DYS病例,采用Methylight方法定量检测胃黏膜组织p16基因甲基化水平,评价其与DYS进展为胃癌风险的关系.结果 在进展为胃癌组,p16基因甲基化百分比中位数(四分位数)为1.30％(0.13％～1.87％),显著高于非进展组的0.67％(0～1.15％),P=0.047.与p16基因低甲基化者相比,高甲基化水平的DYS患者进展为胃癌的风险显著增加,OR-3.67,95％CI为1.31～10.34.进一步分析发现幽门螺杆菌(H.pylori)感染阳性者p16基因甲基化百分比中位数(0.98％)明显高于阴性者(0.01％),P＜0.001;分层分析发现,p16基因高甲基化同时H.pylori感染阳性者进展为胃癌的风险进一步增加,OR=5.14,95％CI为1.57～16.82.通过分析p16基因甲基化水平与DYS病例进展为胃癌的时间关系,发现随着胃癌诊断时间的临近,p16基因甲基化水平有缓慢升高的趋势,但差异未见统计学意义.结论 胃黏膜组织p16基因甲基化水平升高可作为DYS患者发生恶性转化的潜在预警标志物.OBJECTIVE Dysplasia (DYS) is an advanced stage of gastric precancerous,with high risk of malignant transformation.The objective of this study was to explore the association between p16 methylation and risk of gastric cancer (GC),a prospective study was conducted in an area at high risk of GC in Linqu County,Shandong Province.where the proportion of DYS was higher in population.METHODS The methylation levels of p16 were determined by a 115 bp Methylight assay in 101 DYS patients selected from high risk of GC area and with long-term follow-up results to December 31,2015.RESULTS The median of p16 methylation proportions was significantly higher in subjects progressed to GC than those in control group [1.30％ (0.13 ％-1.87 ％) vs 0.67 ％ (0-1.15 ％),P =0.047].Compared with the hypomethylated p16 subjects,the hypermethylated p16 subjects were in higher risk of progression to GC [Odds ratio (OR)..3.67;95％ confidence interval(CI):1.31-10.34].Since higher p16 methylation proportion median was found more often in Helicobacter pylori (H.pylori) positive subjects than that in negative ones (0.98 ％ vs.0.01％,P＜0.001),stratified analysis by H.pylori status further indicated an increased risk of GC progression in H.pylori positive subjects with hypermethylation status of p16 (OR=5.14,95％CI..1.57-16.82).Furthermore,the temporal trend analysis of p16 methylation levels showed a gradually increase of methylation levels with the approaching of GC diagnosis.CONCLUSION The p16 methylation level in gastric mucosa may serve as a potential biomarker for risk of progression to GC in DYS patients.国家自然科学基金面上项目; 北京市科技计划7431-4362