SNP rs17079281 Decreases Lung Cancer Risk Through Creating an YY1-Binding Site to Suppress DCBLD1 Expression

Abstract

Background: Genome-wide association studies (GWAS) have identified numerous genetic polymorphisms that are associated with cancer risk, but their biological function remains largely unknown. Methods: We performed a linkage disequilibrium (LD) analysis on a GWAS-discovered SNP rs9387478 and identified several potentially functional SNPs. We examined the associations of these SNPs with lung cancer in case and control study. Luciferase assay, CHIP-qPCR and CRISPR/Cas9-mediated gene editing experiments were performed to confirm the effect of rs17079281 on gene DCBLD1 expression. Knockdown or upregulation of DCBLD1 in cancer cells were evaluated for oncogenic properties using cell-based functional assays and a mouse xenograft model. Findings: The results suggested that lung cancer risk was associated with SNP rs17079281 and that patients with genotype C/T or T/T had lower risk compared with those with genotype C/C (OR=0.78, 95% CI=0.63-0.98), which was validated with in a case-control study (558 cases and 534 controls) and a meta-analysis of 4403 cases and 5336 controls which included 3 GWASs. YY1 had higher binding-affinity to the T alleles of rs17079281 than to the C alleles, which influenced the expression of DCBLD1 in allele-specific manner. Our study further showed that DCBLD1 promoted lung cancer cell growth by influencing cell cycle. Interpretation: These findings revealed how a risk SNP rs17079281 conferred susceptibility to tumorigenesis and the important role of DCBLD1 in participating the development of lung cancer. Funding: This work was supported by the National Natural Science Foundation of China. Declaration of Interest: The authors declare no potential conflicts of interest. Ethical Approval Statement: The two case-control studies were approved by the ethic review committees at Tianjin Medical University Cancer Hospital and the institutional review board of China Medical University, respectively. Each study subject signed an informed consent before being enrolled in the study in accordance with the Declaration of Helsinki. The animal experiment was approved by the Shanghai Jiao Tong University School of Medicine Animal Ethics Committee and carried out in accordance to the approved protocols.