Functional variants in DCAF4 associated with lung cancer risk in European populations
Functional variants in DCAF4 associated with lung cancer risk in European populations
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DOI：
10.1093/carcin/bgx033
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发表时间：
2017-05-01
期刊：
影响因子：
4.7
通讯作者：
Wei, Qingyi
中科院分区：
文献类型：
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作者：
Liu, Hongliang;Liu, Zhensheng;Wei, Qingyi
Cullin-RING泛素连接酶（CRLs）负责泛素化的底物特异性，在细胞周期控制和DNA损伤反应中起关键作用。在这项研究中，我们评估了115个CRL基因中的16599个SNP与肺癌风险之间的关联，使用了6项已发表的全基因组关联研究（GWAS）的汇总数据，其中包括12160例和16838例欧洲血统。因此，我们在DCAF 4中鉴定了三个独立的SNP，（rs 117781739、rs 12587742和rs 2240980）与肺癌风险相关（比值比分别为0.91、1.09和1.09; 95%可信区间分别为0.88-0.95、1.05-1.14和1.05-1.13; P = 3.99 × 10（-6）、4.97 × 10（-5）和1.44 × 10（-5））。由于SNP rs 12587742位于DCAF 4的启动子区域和一个CpG岛内，我们进一步进行了计算机功能分析，发现rs 12587742变体A等位基因与mRNA表达增加相关（P = 2.20 × 10 ~（-16）、1.79 × 10 ~（-13）和0.001），在脂肪和肺肿瘤组织中分别为P = 2.48 × 10（-9）和0.032）。此外，差异表达分析的证据进一步支持DCAF 4对肺癌的致癌作用，肺鳞癌和腺癌中的mRNA水平均高于邻近正常组织（分别为P = 4.48 x 10（-11）和1.22 x 10（-9））。综上所述，我们的研究结果表明，rs 12587742与肺癌风险增加有关，可能是通过上调mRNA表达和降低DCAF 4的甲基化状态。
Cullin-RING ubiquitin ligases (CRLs) responsible for substrate specificity of ubiquitination play a key role in cell-cycle control and DNA damage response. In this study, we assessed associations between 16 599 SNPs in 115 CRL genes and lung cancer risk by using summary data of six published genome-wide association studies (GWASs) of 12 160 cases and 16 838 cases of European ancestry. As a result, we identified three independent SNPs in DCAF4 (rs117781739, rs12587742 and rs2240980) associated with lung cancer risk (odds ratio = 0.91, 1.09 and 1.09, respectively; 95% confidence interval = 0.88-0.95, 1.05-1.14 and 1.05-1.13, respectively; and P = 3.99 x 10(-6), 4.97 x 10(-5) and 1.44 x 10(-5), respectively) after multiple comparison correction by a false discovery rate < 0.05. Since SNP rs12587742 is located within the promoter region and one CpG island of DCAF4, we further performed in silico functional analyses and found that the rs12587742 variant A allele was associated with an increased mRNA expression (P = 2.20 x 10(-16), 1.79 x 10(-13) and 0.001 in blood cells, normal lung tissues and tumor tissues of lung squamous carcinoma, respectively) and a decreased methylation status (P = 2.48 x 10(-9) and 0.032 in adipose and lung tumor tissues, respectively). Moreover, evidence from differential expression analyses further supported an oncogenic effect of DCAF4 on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (P = 4.48 x 10(-11) and 1.22 x 10(-9), respectively) than in adjacent normal tissues. Taken together, our results suggest that rs12587742 is associated with an increased lung cancer risk, possibly by up-regulating mRNA expression and decreasing methylation status of DCAF4.