{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Liu H"],"funding":["Cancer Research UK","NHGRI NIH HHS","NCI NIH HHS"],"pagination":["541-551"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6074950"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["38(5)"],"pubmed_abstract":["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 × 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 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 × 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 (P = 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 DCAF4 on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (P = 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 DCAF4."],"journal":["Carcinogenesis"],"pubmed_title":["Functional variants in DCAF4 associated with lung cancer risk in European populations."],"pmcid":["PMC6074950"],"funding_grant_id":["R01 CA055769","C1298/A8362","C1298/A8780","U01 HG004446","N01 CN25522","P30 CA023108","HHSN268200782096C","R01 CA092039","R01 CA121197","N01 CN75022","N01 CN25404","N01 CN25524","U01 HG004438","U19 CA148127","R35 CA197449","K07 CA160753","P30 CA014236","R01 CA127219","N01 CN25512","N01 CN25511","N01 CN25476","N01 CN25518","R01 CA111703","N01 CN25516","R01 CA133996","N01 CN25515","N01 CN25514","N01 CN25513"],"pubmed_authors":["Liu H","Stinchcombe TE","Brennan P","Bickeboller H","Caporaso N","Han Y","Christiani DC","Risch A","Ye Y","Rosenberger A","Owzar K","Brhane Y","Bruske I","Amos CI","Liu Z","McLaughlin J","Landi MT","Wei Q","Hung RJ","Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team","Wang Y","Houlston RS","Wu X"],"additional_accession":[]},"is_claimable":false,"name":"Functional variants in DCAF4 associated with lung cancer risk in European populations.","description":"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 × 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 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 × 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 (P = 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 DCAF4 on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (P = 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 DCAF4.","dates":{"release":"2017-01-01T00:00:00Z","publication":"2017 May","modification":"2020-11-19T09:40:42Z","creation":"2019-03-26T23:50:50Z"},"accession":"S-EPMC6074950","cross_references":{"pubmed":["28383684"],"doi":["10.1093/carcin/bgx033"]}}