胃癌患者术前腹腔冲洗液游离DNA中TIMP-3基因甲基化与腹腔微转移的相关性

Correlation between TIMP-3 hypermethylation in peritoneal lavage fluid and peritoneal micrometastasis in patients with gastric cancer

目的:探讨胃癌患者术前腹腔冲洗液中组织金属蛋白酶抑制因子-3(tissue inhibitor ofmetalloproteinase 3,TIMP-3)基因启动子CpG岛异常甲基化与腹腔微转移的相关性.方法:应用甲基化特异性实时荧光聚合酶链反应技术检测92例胃癌患者术前腹腔冲洗液中TIMP-3基因启动子CpG岛甲基化状态,分析TIMP-3基因异常甲基化与患者临床病理参数及预后之间的关系.结果:在92例胃癌患者术前腹腔冲洗液标本中,有49(53.26%)例检测到了TIMP-3基因甲基化,且TIMP-3基因甲基化与肿瘤大小(P=0.013)、静脉侵犯(P=0.030)和远处转移(P=0.013)间均存在相关性,与生长方式、分化程度、淋巴管侵犯、淋巴结转移、浸润深度和临床分期间存在显著相关性(P=0.000),而与性别、年龄、Helicobacter pylori感染状况以及肿瘤部位等不存在相关性(P分别为0.833、0.236、0.300、0.236).生存分析发现TIMP-3基因非甲基化患者具有独立的生存优势(P=0.000).结论:胃癌患者术前腹腔冲洗液游离DNA中TIMP-3基因异常甲基化可反映腹腔微转移发生,并提示预后不良.

AIM： To investigate the relationship between ectopic methylation of the tissue inhibitor of metalloproteinase 3（TIMP-3） gene in preoperative peritoneal lavage fluid and peritoneal micrometastasis in patients with gastric cancer.METHODS： Methylation-specific real-time polymerase chain reaction（qMSP） was used to detect the methylation status of CpG islands in the promoter of the TIMP-3 gene in 92 preoperative peritoneal lavage fluid samples.The relationship between ectopic methylation of the TIMP-3 gene and clinicopathologic features and prognosis was then analyzed.RESULTS： Abberant TIMP-3 gene methylation occurred in 49（53.26%） samples.Correlation was observed between TIMP-3 gene methylation and tumor size（P = 0.015）,distant metastasis（P = 0.013） and venous invasion（P = 0.030）,and there is a significant correlation between TIMP-3 gene methylation and tumor growth pattern,differentiation,lymph node metastasis and clinical stage（P = 0.000）.However,the level of TIMP-3 methylation had no significant association with patient’s gender and age,Helicobacter pylori infection,or lesion location（P = 0.833,0.236,0.300 0.236,respectively）.Survival analysis indicate that patients who had no TIMP-3 gene methylation had a higher survival rate（P = 0.000）.CONCLUSION： Ectopic methylation of TIMP-3 gene in preoperative lavage fluid samples is associated with peritoneal micrometastasis and poor prognosis in patients with gastric cancer.