Dai Juncheng, Zhu Meng, Wang Cheng, Shen Wei, Zhou Wen, Sun Jie, Liu Jia, Jin Guangfu, Ma Hongxia, Hu Zhibin, Lin Dongxin, Shen Hongbing
1] Department of Epidemiology and Biostatistics and Ministry of Education (MOE), Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China [2] Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China.
Department of Epidemiology and Biostatistics and Ministry of Education (MOE), Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Sci Rep. 2015 Jan 16;5:7833. doi: 10.1038/srep07833.
Genome-wide association studies identified genetic susceptibility variants mostly lie outside of protein-coding regions. It suggested variants located at transcriptional regulatory region should play an important role in cancer carcinogenesis including lung cancer. In the present study, we systematically investigated the associations between the variants in the binding sites of an extensive transcription factor CTCF and lung cancer risk in Chinese population. A two-stage case-control design was conducted to evaluate the variants located at the uniform CTCF ChIP-seq peaks in a Chinese population (2,331 vs 3,077; 1,115 vs 1,346). The ChIP-seq data for CTCF, specified on lung cancer cell line A549, were downloaded from ENCODE database. Imputation was performed to increase the genome coverage in the CTCF binding regions. Three variants in CTCF binding sites were found to associate with lung cancer risk in the first stage. Further replication revealed a novel single nucleotide polymorphism rs60507107 was significantly associated with increased risk of lung cancer in two stages (Additive model: OR = 1.19, 95%CI = 1.11-1.27, P = 6.98 × 10(-7)). Our results indicate that rs60507107 in the binding site of CTCF is associated with an increased risk of lung cancer. This may further advance our understanding of regulatory DNA sequences in cancer development.
全基因组关联研究发现，遗传易感性变异大多位于蛋白质编码区域之外。这表明位于转录调控区域的变异在包括肺癌在内的癌症致癌过程中应发挥重要作用。在本研究中，我们系统地调查了广泛的转录因子CTCF结合位点变异与中国人群肺癌风险之间的关联。采用两阶段病例对照设计，评估中国人群中位于统一CTCF ChIP-seq峰上的变异（2331例对3077例；1115例对1346例）。从ENCODE数据库下载了针对肺癌细胞系A549指定的CTCF的ChIP-seq数据。进行了填充以增加CTCF结合区域的基因组覆盖范围。在第一阶段发现CTCF结合位点的三个变异与肺癌风险相关。进一步的重复研究揭示了一个新的单核苷酸多态性rs60507107在两个阶段均与肺癌风险增加显著相关（加性模型：OR = 1.19，95%CI = 1.11 - 1.27，P = 6.98×10(-7)）。我们的结果表明，CTCF结合位点中的rs60507107与肺癌风险增加相关。这可能会进一步推动我们对癌症发展中调控DNA序列的理解。
