title: Functional variants in DCAF4 associated with lung cancer risk in European populations.
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.
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Zhensheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Stinchcombe
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.affiliation: Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Younghun
authors.initials: Y
authors.lastname: Han
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5,Canada.
authors.forename: Rayjean J
authors.initials: RJ
authors.lastname: Hung
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5,Canada.
authors.forename: Yonathan
authors.initials: Y
authors.lastname: Brhane
authors.affiliation: Public Health Ontario, Toronto, Ontario M5T 3L9, Canada.
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.affiliation: Genetic Epidemiology Group, International Agency for Research on Cancer, 69372 Lyon, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.affiliation: Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.affiliation: Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Rosenberger
authors.affiliation: Division of Genetics and Epidemiology, the Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Caporaso
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Landi
authors.affiliation: Helmholtz Centre Munich, German Research Centre for Environmental Health, Institute of Epidemiology I, 85764 Neuherberg, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Brüske
authors.affiliation: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria.
authors.forename: Angela
authors.initials: A
authors.lastname: Risch
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Massachusetts General Hospital, Boston, MA 02114, USA and.|Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.affiliation: Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D019295:Computational Biology / Q000379:methods; D019175:DNA Methylation; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012307:Risk Factors; D044465:White People / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C574006:DCAF4 protein, human