Tessema Mathewos, Yu Yang Y, Stidley Christine A, Machida Emi O, Schuebel Kornel E, Baylin Stephen B, Belinsky Steven A
Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive Southeast, Albuquerque, NM 87108, USA.
Carcinogenesis. 2009 Jul;30(7):1132-8. doi: 10.1093/carcin/bgp114. Epub 2009 May 12.
Aberrant promoter hypermethylation is one of the major mechanisms in carcinogenesis and some critical growth regulatory genes have shown commonality in methylation across solid tumors. Twenty-six genes, 14 identified through methylation in colon and breast cancers, were evaluated using primary lung adenocarcinomas (n = 175) from current, former and never smokers. Tumor specificity of methylation was validated through comparison of 14 lung cancer cell lines to normal human bronchial epithelial cells derived from bronchoscopy of 20 cancer-free smokers. Twenty-five genes were methylated in 11-81% of primary tumors. Prevalence for methylation of TNFRSF10C, BHLHB5 and BOLL was significantly higher in adenocarcinomas from never smokers than smokers. The relation between methylation of individual genes was examined using pairwise comparisons. A significant association was seen between 138 (42%) of the possible 325 pairwise comparisons. Most notably, methylation of MMP2, BHLHB4 or p16 was significantly associated with methylation of 16-19 other genes, thus predicting for a widespread methylation phenotype. Kaplan-Meier log-rank test and proportional hazard models identified a significant association between methylation of SULF2 (a pro-growth, -angiogenesis and -migration gene) and better patient survival (hazard ratio = 0.23). These results demonstrate a high degree of commonality for targeted silencing of genes between lung and other solid tumors and suggest that promoter hypermethylation in cancer is a highly co-ordinated event.
异常的启动子高甲基化是致癌作用的主要机制之一，一些关键的生长调节基因在实体瘤的甲基化方面表现出共性。使用来自现吸烟者、既往吸烟者和从不吸烟者的原发性肺腺癌（n = 175），对通过结肠癌和乳腺癌甲基化鉴定出的26个基因中的14个进行了评估。通过将14种肺癌细胞系与来自20名无癌吸烟者支气管镜检查的正常人支气管上皮细胞进行比较，验证了甲基化的肿瘤特异性。25个基因在11% - 81%的原发性肿瘤中发生甲基化。从不吸烟者的腺癌中TNFRSF10C、BHLHB5和BOLL的甲基化发生率显著高于吸烟者。使用成对比较检查单个基因甲基化之间的关系。在325个可能的成对比较中，有138个（42%）存在显著关联。最值得注意的是，MMP2、BHLHB4或p16的甲基化与其他16 - 19个基因的甲基化显著相关，从而预测出广泛的甲基化表型。Kaplan - Meier对数秩检验和比例风险模型确定SULF2（一种促进生长、血管生成和迁移的基因）的甲基化与患者更好的生存率之间存在显著关联（风险比 = 0.23）。这些结果表明，肺和其他实体瘤之间基因靶向沉默具有高度共性，并表明癌症中的启动子高甲基化是一个高度协调的事件。
