p16、DAPK和RARβ基因启动子CpG岛甲基化与非小细胞肺癌临床特征的关系

Relationship between promoter methylation of p16, DAPK and RARβ genes and the clinical data of non-small cell lung cancer

目的研究非小细胞肺癌（non-smal cell lung cancer，NSCLC）患者p16、DAPK和RARβ启动子区CpG岛甲基化对临床特征的影响，探讨其与吸烟的关系。方法应用甲基化特异性PCR检测200例原发性NSCLC组织和相应正常组织中p16，DAPK和RARβ基因启动子区CpG岛甲基化状况。结果p16、DAPK和RARβ基因甲基化在癌组织中的检出率分别为51．0％、60．0％和58．0％，均高于其在正常组织中的检出率（分别为12．5％，11．5％和15．0％；P〈0．05）。非条件Logistic回归显示，癌组织p16基因甲基化与年龄和病例组织类型有关（P〈0．05）；癌组织DAPK基因甲基化与年龄、性别、临床分类有关（P〈0．05）；而癌组织RARβ基因甲基化与临床分类和TNM（tumor node metastasis）分期相关（P〈0．05）。癌组织p16基因甲基化与DAPK基因甲基化之间存在交互作用（0R=1.987，95％CI：1．055～3．743）。吸烟者癌组织p16和DAPK基因甲基化的0R值分别为3．139（95％CI：1．046～9．419）和3．585（95％CI：1．270～10．123），未发现癌组织RARβ基因甲基化与吸烟有关。结论p16，DAPK和RARβ甲基化与NSCLC患者临床特征关系密切。吸烟与p16和DAPK基因甲基化有关。

Objective To investigate the effects of promoter methylation of p16 , death-associated protein kinase （DAPK） and retinoic acid receptor-β （RARβ） genes on clinical data in non-small cell lung cancers, and to study the effect of smoking on the risk of gene methylation. Methods The promoter methylation of p16 , DAPK and RARβ genes in 200 primary non-small cell lung cancers and the corresponding nonmalignant lung tissues were determined by methylation-specific PCR. Results Methylation in the tumor tissues was detected in 51.0% for p16 , 60.0% for DAPK, and 58.0% for RARβ gene, with significant differences （P〈 0. 05） when compared with those in the corresponding nonmalignant tissues （12.5%,11.5% and 15.0%） respectively, p16 gene methylation in tumor tissue was associated with age significantly in unconditional logistic regression analysis （P〈（0.01） and histologic type （P〈0.05）. DAPK gene methylation in tumor tissue was associated significantly with age （P〈0.05）, gender （P〈0.05） and clinical type （P〈0. 05）. RARβ gene methylation in tumor tissue was associated with clinical type （P〈 0.05） and tumor stage （P〈0.05） significantly. The interaction odds ratio （OR） for the gene-gene interaction in tumor tissue between p16 and DAPK was 1. 987 （95%CI： 1. 055-3. 743）. The results of the gene-smoking analyses revealed that a relationship existed between cigarette smoking and p16 gene methylation （OR： 3. 139, 95 %CI：1. 046-9. 419）, the OR for the relationship of DAPK gene methylation and cigarette smoking was 3. 585 （95 %CI：1. 270-10. 123）in tumor tissue. The RARβ gene methylation did not differ based on the smoking status of patients in tumor tissue. Conclusion Thep16 , DAPK and RARβ genes methylation are strongly associated with clinical data of non-small cell lung cancer, and methylation of p16 and DAPK genes are associated with tobacco smoking.