Functional variants in DCAF4 associated with lung cancer risk in European populations

<span class="paragraphSection"><div class="boxTitle">Abstract</div>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 <span style="font-style:italic;">DCAF4</span> (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 <span style="font-style:italic;">P</span> = 3.99 × 10^–6, 4.97 × 10^–5 and 1.44 × 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 <span style="font-style:italic;">DCAF4</span>, we further performed <span style="font-style:italic;">in silico</span> functional analyses and found that the rs12587742 variant A allele was associated with an increased mRNA expression (<span style="font-style:italic;">P</span> = 2.20 × 10⁻¹⁶, 1.79 × 10⁻¹³ and 0.001 in blood cells, normal lung tissues and tumor tissues of lung squamous carcinoma, respectively) and a decreased methylation status (<span style="font-style:italic;">P</span> = 2.48 × 10⁻⁹ and 0.032 in adipose and lung tumor tissues, respectively). Moreover, evidence from differential expression analyses further supported an oncogenic effect of <span style="font-style:italic;">DCAF4</span> on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (<span style="font-style:italic;">P</span> = 4.48 × 10⁻¹¹ and 1.22 × 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 <span style="font-style:italic;">DCAF4</span>.</span>

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2qWqpR9
via IFTTT