p16基因高甲基化在胃癌发展中的作用

Correlation of p16 hypermethylation with tumorigenesis and the development of gastric cancer

目的:通过检测胃癌、癌前病变和正常对照组中p16基因启动子区CpG岛甲基化水平及其表达,并结合临床病理资料,分析他们在胃癌发生、发展中的作用.方法:用甲基化特异性聚合酶链反应(methylation-specific PCR,MSP)检测41例胃癌组织、40例癌前病变组织和38例正常对照组织中p16基因启动子5′CpG岛甲基化;应用免疫组化检测基因的蛋白表达.结果:胃癌组织中p16基因甲基化阳性率为56.1%(23/41),癌前病变组织中为17.5%(7/40),而正常对照组织中为2.6%(1/38),前组与后两组之间的差异有显著性(P<0.05).胃癌组织中p16基因表达阳性率为51.2%,癌前病变组织中为90.0%,正常对照组织中为100.0%,前组与后两组之间的差异有显著性(P<0.05).低分化型胃癌组织中的p16基因甲基化阳性率明显高于高分化型(81.3%vs 40.0%,P<0.05).有淋巴结转移的胃癌组织中,p16基因甲基化阳性率与无转移组的差异有显著性(81.0%vs 30.0%,P<0.05).浸润深达浆膜层的胃癌组织中,甲基化阳性率与未达浆膜层组无统计学差异(60.0%vs 52.4%,P>0.05).胃癌组织中p16基因甲基化阳性组的蛋白表达阳性率显著低于甲基化阴性组(26.1%vs 83.3%,P<0.01).结论:胃癌组织中存在有p16基因启动子5′CpG岛高甲基化,并导致其基因表达率显著低于正常对照及癌前病变组织.p16基因的高甲基化与胃癌分化程度、淋巴结转移相关.p16基因甲基化的发生,从正常、癌前病变到胃癌有逐渐增加的趋势,提示其基因CpG岛高甲基化有可能作为诊断早期胃癌的一项较为敏感的指标.

AIM： Transcriptional silencing induced by hypermethylation of CpG islands in the promoter regions of genes is believed to be an important mechanism underlying tumorigenesis. This study explored the correlation of p16 hypermethylation with tumorigenesis and the development of gastric cancer. METHODS： Methylation-specific polymerase chain reaction （MSP） was used to detect methylation of the p16 gene in 41 specimens of gastric cancer, 40 specimens of premalignant lesions and 38 normal control specimens. The expression of p16 protein was detected by immunohistochemistry. RESULTS： The positive rate of p16 gene methylation was significantly higher in gastric cancer than in premalignant lesions and normal control specimens （56.1% vs 17.5%, 2.63%, both P 〈 0.05）. The positive rate of p16 gene expression was significantly lower in gastric cancer than in premalignant lesions and normal control specimens （51.2% vs 90.0%, 100.0%, both P 〈 0.05）. The positive rate of p16 gene methylation was significantly higher in poorly differentiated cancer than in well-differentiated cancer （81.2% vs 40.0%, P 〈 0.05）. The positive rate of p16 gene methylation was significantly higher in gastric cancers with metastasis to the lymph node than in those without metastasis to the lymph node （80.9% vs 30.0%, P 〈 0.05）. The positive rate of p16 gene methylation was higher in gastric cancers with invasion to the serosa than in those without invasion to the serosa （60.0% vs 52.4%, P 〉 0.05）. The positive rate of p16 protein expression in gastric cancers with p16 gene methylation was significantly lower than that in gastric cancers without p16 gene methylation （26.1% vs 83.3%, P 〈 0.05）. CONCLUSION： Hypermethylation of CpG islands in the promoter of the p16 gene exists in gastric cancer and can downregulate p16 expression. The level of hypermethylation of these CpG islands increases from premalignant lesions through lower degrees of malignancy to higher degrees of malignancy, and might be involved in tumorigenesis and the development of gastric cancer.