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: Hongliang Liu, Zhensheng Liu, Yanru Wang, Thomas E Stinchcombe, Kouros Owzar, Younghun Han, Rayjean J Hung, Yonathan Brhane, John McLaughlin, Paul Brennan, Heike Bickeböller, Albert Rosenberger, Richard S Houlston, Neil Caporaso, Maria T Landi, Irene Brüske, Angela Risch, Xifeng Wu, Yuanqing Ye, David C Christiani, Christopher I Amos, Qingyi Wei, Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team
• Journal: Carcinogenesis (Carcinogenesis) Vol. 38 Issue 5 Pg. 541-551 (05 01 2017) ISSN: 1460-2180 [Electronic] England
• PMID: 28383684 (Publication Type: Journal Article, Meta-Analysis)
• Copyright: © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Carrier Proteins
• DCAF4 protein, human

Topics

• Carrier Proteins (genetics)
• Case-Control Studies
• Computational Biology (methods)
• DNA Methylation
• Gene Expression Profiling
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genetic Variation
• Genome-Wide Association Study
• Humans
• Linkage Disequilibrium
• Lung Neoplasms (genetics, pathology)
• Odds Ratio
• Polymorphism, Single Nucleotide
• Risk
• Risk Factors
• White People (genetics)