Kang Xiaozheng, Liu Hongliang, Onaitis Mark W, Liu Zhensheng, Owzar Kouros, Han Younghun, Su Li, Wei Yongyue, Hung Rayjean J, Brhane Yonathan, McLaughlin John, Brennan Paul, Bickeböller Heike, Rosenberger Albert, Houlston Richard S, Caporaso Neil, Landi Maria Teresa, Heinrich Joachim, Risch Angela, Wu Xifeng, Ye Yuanqing, Christiani David C, Amos Christopher I, Wei Qingyi
Duke Cancer Institute and.
Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, 905 S. LaSalle Street, Durham, NC 27710, USA.
Carcinogenesis. 2016 Mar;37(3):280-289. doi: 10.1093/carcin/bgw014. Epub 2016 Feb 10.
Centrosome abnormalities are often observed in premalignant lesions and in situ tumors and have been associated with aneuploidy and tumor development. We investigated the associations of 9354 single-nucleotide polymorphisms (SNPs) in 106 centrosomal genes with lung cancer risk by first using the summary data from six published genome-wide association studies (GWASs) of the Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16 838 controls) and then conducted in silico replication in two additional independent lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26,380 controls). A total of 44 significant SNPs with false discovery rate (FDR) ≤ 0.05 were mapped to one novel gene FGFR1OP and two previously reported genes (TUBB and BRCA2). After combined the results from TRICL with those from Harvard and deCODE, the most significant association (P combined = 8.032 × 10(-6)) was with rs151606 within FGFR1OP. The rs151606 T>G was associated with an increased risk of lung cancer [odds ratio (OR) = 1.10, 95% confidence interval (95% CI) = 1.05-1.14]. Another significant tagSNP rs12212247 T>C (P combined = 9.589 × 10(-6)) was associated with a decreased risk of lung cancer (OR = 0.93, 95% CI = 0.90-0.96). Further in silico functional analyzes revealed that rs151606 might affect transcriptional regulation and result in decreased FGFR1OP expression (P trend = 0.022). The findings shed some new light on the role of centrosome abnormalities in the susceptibility to lung carcinogenesis.
中心体异常在癌前病变和原位肿瘤中经常被观察到，并且与非整倍体和肿瘤发展有关。我们首先使用来自肺癌跨学科研究（TRICL）的六项已发表的全基因组关联研究（GWAS）的汇总数据（12160例病例和16838例对照），研究了106个中心体基因中的9354个单核苷酸多态性（SNP）与肺癌风险的关联，然后在哈佛大学另外两项独立的肺癌GWAS（984例病例和970例对照）和deCODE（1319例病例和26380例对照）中进行了计算机模拟复制。共有44个错误发现率（FDR）≤0.05的显著SNP被定位到一个新基因FGFR1OP和两个先前报道的基因（TUBB和BRCA2）。将TRICL的结果与哈佛大学和deCODE的结果合并后，最显著的关联（P合并 = 8.032×10^(-6)）是与FGFR1OP内的rs151606相关。rs151606 T>G与肺癌风险增加相关[比值比（OR） = 1.10，95%置信区间（95%CI） = 1.05 - 1.14]。另一个显著的标签SNP rs12212247 T>C（P合并 = 9.589×10^(-6)）与肺癌风险降低相关（OR = 0.93，95%CI = 0.90 - 0.96）。进一步的计算机模拟功能分析表明，rs151606可能影响转录调控并导致FGFR1OP表达降低（P趋势 = 0.022）。这些发现为中心体异常在肺癌发生易感性中的作用提供了一些新的线索。
