Qin Hualong, Zhu Jianjie, Zeng Yuanyuan, Du Wenwen, Shen Dan, Lei Zhe, Qian Qian, Huang Jian-An, Liu Zeyi
Department of Cardiothoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Oncotarget. 2017 Jan 31;8(5):8330-8341. doi: 10.18632/oncotarget.14177.
DNA methylation may epigenetically inactivate tumor suppressor genes in NSCLC. As the human 8-oxoguanine DNA glycosylase (hOGG1) gene promoter is frequently methylated in NSCLC, we evaluated whether genetic or epigenetic alterations of hOGG1 are associated with increased risk of non-small cell lung cancer. Three hOGG1 haplotype-tagging SNPs (htSNP) were genotyped in PCR-restriction fragment length polymorphism assays, and one htSNP was genotyped in a PCR-single-strand conformation polymorphism assay in case-control studies of 217 NSCLC patients and 226 healthy controls. The methylation profiles of peripheral blood mononuclear cell specimens from 121 NSCLC patients and 121 controls were determined through methylation-specific PCR of hOGG1. No differences in allele or genotype frequencies between NSCLC patients and controls were observed at any of the four polymorphic sites (rs159153, rs125701, rs1052133, and rs293795). However, hOGG1 methylation-positive carriers had a 2.25-fold greater risk of developing NSCLC (adjusted odds ratio: 2.247; 95% confidence interval: 1.067-4.734; P = 0.03) than methylation-free subjects. Furthermore, the demethylating agent 5-aza-2'-deoxycytidine restored hOGG1 expression in NSCLC cell lines. These data provide strong evidence of an association between peripheral blood mononuclear cell hOGG1 methylation and the risk of NSCLC in a Chinese population.
DNA甲基化可能通过表观遗传方式使非小细胞肺癌（NSCLC）中的肿瘤抑制基因失活。由于人8-氧代鸟嘌呤DNA糖基化酶（hOGG1）基因启动子在NSCLC中经常发生甲基化，我们评估了hOGG1的基因或表观遗传改变是否与非小细胞肺癌风险增加相关。在217例NSCLC患者和226例健康对照的病例对照研究中，通过聚合酶链反应-限制性片段长度多态性分析对3个hOGG1单倍型标签单核苷酸多态性（htSNP）进行基因分型，并通过聚合酶链反应-单链构象多态性分析对1个htSNP进行基因分型。通过hOGG1的甲基化特异性聚合酶链反应确定了121例NSCLC患者和121例对照的外周血单个核细胞标本的甲基化谱。在4个多态性位点（rs159153、rs125701、rs1052133和rs293795）中的任何一个位点，NSCLC患者和对照之间的等位基因或基因型频率均未观察到差异。然而，hOGG1甲基化阳性携带者发生NSCLC的风险比无甲基化者高2.25倍（调整后的优势比：2.247；95%置信区间：1.067 - 4.734；P = 0.03）。此外，去甲基化剂5-氮杂-2'-脱氧胞苷可恢复NSCLC细胞系中hOGG1的表达。这些数据为中国人群中外周血单个核细胞hOGG1甲基化与NSCLC风险之间的关联提供了有力证据。
