Genetic determinants for promoter hypermethylation in the lungs of smokers: a candidate gene-based study.
Genetic determinants for promoter hypermethylation in the lungs of smokers: a candidate gene-based study.
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DOI：
10.1158/0008-5472.can-11-3194
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发表时间：
2012-02-01
期刊：
影响因子：
11.2
通讯作者：
Belinsky SA
中科院分区：
文献类型：
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作者：
Leng S;Stidley CA;Liu Y;Edlund CK;Willink RP;Han Y;Landi MT;Thun M;Picchi MA;Bruse SE;Crowell RE;Van Den Berg D;Caporaso NE;Amos CI;Siegfried JM;Tesfaigzi Y;Gilliland FD;Belinsky SA
肺癌脱落细胞中抑癌基因启动子甲基化检测对早期肺癌的预测价值。在这里，我们确定了这种表观遗传过程的遗传决定因素，并研究了它们对基因调控的生物学效应。一个两阶段的方法，包括发现和复制，以评估启动子超甲基化的12个基因面板和40个基因的致癌物质代谢，甲基化的调节，和DNA损伤反应的Lovelace吸烟者队列（n = 1434）的成员中参与的常见变异之间的关联。使用原代支气管上皮细胞对三种鉴定的变体进行分子验证。在TP53、LIG1和BIK中，rs1641511、rs3730859和rs1883264分别具有研究范围内的显著性（P <8.2 × 10 − 5）。这些SNPs与原代支气管上皮细胞中相应基因的表达改变显著相关。此外，LIG1中的rs3730859也与白人吸烟者肺癌风险增加中度相关。总之，我们的研究结果表明，DNA复制和凋亡途径的遗传变异影响吸烟者呼吸消化道基因启动子高甲基化的倾向。将基因启动子高甲基化的遗传标记物与临床和体细胞标记物相结合可能会改善肺癌的风险评估模型。
The detection of tumor suppressor gene promoter methylation in sputum-derived exfoliated cells predicts early lung cancer. Here we identified genetic determinants for this epigenetic process and examined their biological effects on gene regulation. A two-stage approach involving discovery and replication was employed to assess the association between promoter hypermethylation of a 12-gene panel and common variation in 40 genes involved in carcinogen metabolism, regulation of methylation, and DNA damage response in members of the Lovelace Smokers Cohort (n=1434). Molecular validation of three identified variants was conducted using primary bronchial epithelial cells. Association of study-wide significance (P<8.2×10−5) was identified for rs1641511, rs3730859, and rs1883264 in TP53, LIG1, and BIK, respectively. These SNPs were significantly associated with altered expression of the corresponding genes in primary bronchial epithelial cells. In addition, rs3730859 in LIG1 was also moderately associated with increased risk for lung cancer among Caucasian smokers. Together, our findings suggest that genetic variation in DNA replication and apoptosis pathways impacts the propensity for gene promoter hypermethylation in the aerodigestive tract of smokers. The incorporation of genetic biomarkers for gene promoter hypermethylation with clinical and somatic markers may improve risk assessment models for lung cancer.