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SNP rs17079281 decreases lung cancer risk through creating an YY1-binding site to suppress DCBLD1 expression.

ABSTRACT: Genome-wide association studies (GWAS) have identified numerous genetic variants that are associated with lung cancer risk, but the biological mechanisms underlying these associations remain largely unknown. Here we investigated the functional relevance of a genetic region in 6q22.2 which was identified to be associated with lung cancer risk in our previous GWAS. We performed linkage disequilibrium (LD) analysis and bioinformatic prediction to screen functional SNPs linked to a tagSNP in 6q22.2 loci, followed by two case-control studies and a meta-analysis with 4403 cases and 5336 controls to identify if these functional SNPs were associated with lung cancer risk. A novel SNP rs17079281 in the DCBLD1 promoter was identified to be associated with lung cancer risk in Chinese populations. Compared with those with C allele, patients with T allele had lower risk of adenocarcinoma (adjusted OR?=?0.86; 95% CI: 0.80-0.92), but not squamous cell carcinoma (adjusted OR?=?0.99; 95% CI: 0.91-1.10), and patients with the C/T or T/T genotype had lower levels of DCBLD1 expression than those with C/C genotype in lung adenocarcinoma tissues. We performed functional assays to characterize its biological relevance. The results showed that the T allele of rs17079281 had higher binding affinity to transcription factor YY1 than the C allele, which suppressed DCBLD1 expression. DCBLD1 behaved like an oncogene, promoting tumor growth by influencing cell cycle progression. These findings suggest that the functional variant rs17079281C>T decreased lung adenocarcinoma risk by creating an YY1-binding site to suppress DCBLD1 expression, which may serve as a biomarker for assessing lung cancer susceptibility.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7220863 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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SNP rs17079281 decreases lung cancer risk through creating an YY1-binding site to suppress DCBLD1 expression.

Wang Yu Y Ma Rongna R Liu Ben B Kong Jinyu J Lin Hongyan H Yu Xiao X Wang Ruoyang R Li Lei L Gao Ming M Zhou Baosen B Mohan Man M Yu Herbert H Hou Zhaoyuan Z Shen Hongbin H Qian Biyun B

Oncogene 20200330 20

Genome-wide association studies (GWAS) have identified numerous genetic variants that are associated with lung cancer risk, but the biological mechanisms underlying these associations remain largely unknown. Here we investigated the functional relevance of a genetic region in 6q22.2 which was identified to be associated with lung cancer risk in our previous GWAS. We performed linkage disequilibrium (LD) analysis and bioinformatic prediction to screen functional SNPs linked to a tagSNP in 6q22.2 ...[more]

PMID: 32231272

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Project description:ObjectiveReceptor tyrosine kinases (RTK) are relevant therapeutic targets in the treatment of lung cancer. Germline susceptibility variants that influence these RTKs may provide new insights into their regulation. rs9387478 is located in the genomic interval between two RTK-genes ROS1/DCBLD1, of which ROS1 alterations are implicated in lung carcinogenesis and treatment response while the latter remains poorly understood.Materials and methodsVenous blood was drawn from 100 control and 231 case subjects. Genotype was scored by restriction fragment length polymorphism (RFLP), PCR amplification followed by HindIII digestion. Logistic regression was applied to compare the association between variables. Survival curve was plotted to draw a correlation between the genotype and overall survival. Also, eQTL and chromatin state changes were analyzed and correlated with the survival of patients using available datasets.ResultsIn our population smoking correlated significantly with lung cancer [OR= 2.607] with the presence of the minor allele 'A' enhancing the nicotine dependence [CA (OR=3.23)]. Individuals with homozygous risk allele 'A' had a higher chance of developing lung cancer [OR=2.65] than individuals with CA/CC implying a recessive model of association. Patients with CC/CA genotype had better overall survival than patients with AA genotype [161 days/142 days vs 54 days, p=0.005]. The homozygous risk allele was significantly associated with increased DCBLD1 and ROS1 expression in lung cancer, with enriched active histone marks due to the polymorphism. Interestingly, increased DCBLD1 expression was associated with poor outcomes in lung cancer.ConclusionOverall, our study provides strong evidence that rs9387478 is significantly associated with both nicotine dependence and lung cancer in our North Indian cohort. The association of the SNP with prognostic genes, DCBLD1 and ROS1 make rs9387478 a promising prognostic marker in the North Indian population. The results obtained are significant, however, the study needs to be performed in a larger sample size.

Dataset Information

SNP rs17079281 decreases lung cancer risk through creating an YY1-binding site to suppress DCBLD1 expression.

Publications

SNP rs17079281 decreases lung cancer risk through creating an YY1-binding site to suppress DCBLD1 expression.

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