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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 Linli County, Shandong Province, is one of the high incidence areas of stomach cancer in the northern part of China. The proportion of gastric dysplasia (DYS) in the population is high. DYS is an advanced stage of gastric mucosal precancerous lesions with significant malignant transformation potential. This study was to explore the relationship between methylation of p16 gene and malignant transformation of DYS and to verify its value as an early marker of gastric cancer. Methods Based on the long-term gastroscope follow-up cohort of gastric cancer, 101 cases of DYS from the high incidence of gastric cancer in Linli County of Shandong Province were followed up to December 31, 2015. Methylight method was used to quantitatively detect the methylation level of p16 gene in gastric mucosa, To evaluate its relationship with the progression of DYS to the risk of gastric cancer. Results The median percentage of methylation of p16 gene was 1.30% (0.13% -1.87%) in gastric cancer group, which was significantly higher than 0.67% (0-1.15%) in non-advanced group and P = 0.047. The risk of progression to gastric cancer was significantly higher in patients with hypermethylation compared with patients with hypomethylation of p16, OR = 3.67, 95% CI 1.31 to 10.34. Further analysis found that the positive rate of p16 gene methylation in H.pylori infection was significantly higher than that in the negative (0.01%) (P <0.001). Hierarchical analysis showed that the p16 gene methylation At the same time, H.pylori infection was further increased in patients with gastric cancer, OR = 5.14, 95% CI 1.57-16.82. By analyzing the relationship between the methylation level of p16 gene and the progress of gastric cancer in patients with DYS, it was found that the methylation level of p16 increased slowly with the approaching time of gastric cancer diagnosis, but the difference was not statistically significant. Conclusion The increased methylation level of p16 in gastric mucosa may be a potential marker of malignant transformation in patients with DYS.