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A genetic polymorphism in pre-miR-27a confers clinical outcome of non-small cell lung cancer in a Chinese population.

ABSTRACT: BACKGROUND: Recent evidence indicates that microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Single nucleotide polymorphisms (SNPs) at miRNA genes can influence the maturation of miRNAs or miRNA-mediated transcriptional regulation. Our objective was to investigate the association of SNPs in deregulated miRNAs with clinical outcome in patients with non-small cell lung cancer (NSCLC) in a Chinese population. METHODS: Deregulated miRNAs in NSCLC and their SNPs were identified through public databases. A single SNP, rs895819 in pre-miR-27a, was found suitable for selection. TaqMan assays were performed for genotyping and to assess the effect on the overall survival (OS) and chemotherapy response in 576 NSCLC patients. RESULTS: Log-rank test and Cox regression analysis indicated that the G allele of rs895819 was associated with shorter survival and increased risk of death in NSCLC [dominant model: 22.0 vs. 46.0 months, P<0.001; adjusted hazard ratio (HR)?=?1.71, 95% confidential interval (CI): 1.12-2.26]. Further stepwise regression analysis suggested that this SNP was an independently unfavorable factor for the prognosis of NSCLC and the effect remained significant in subgroup analysis stratified by clinical parameters and treatment status. Moreover, multivariate logistic regression analysis showed that the subjects with AG/GG genotypes of rs895819 had significantly decreased response rate to platinum-based chemotherapy compared to those with the AA genotype. CONCLUSION: Our results suggest that the pre-miR-27a rs895819 polymorphism may influence NSCLC patients' clinical outcome. Further large sample studies should be used to validate our findings.

SUBMITTER: Xu J

PROVIDER: S-EPMC3819265 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A genetic polymorphism in pre-miR-27a confers clinical outcome of non-small cell lung cancer in a Chinese population.

Xu Jiali J Yin Zhiqiang Z Shen Hong H Gao Wen W Qian Yingying Y Pei Dong D Liu Lingxiang L Shu Yongqian Y

PloS one 20131106 11

<h4>Background</h4>Recent evidence indicates that microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Single nucleotide polymorphisms (SNPs) at miRNA genes can influence the maturation of miRNAs or miRNA-mediated transcriptional regulation. Our objective was to investigate the association of SNPs in deregulated miRNAs with clinical outcome in patients with non-small cell lung cancer (NSCLC) in a Chinese population.<h4>Methods</h4>Deregulated miRNAs in NSCLC and their SNPs were id ...[more]

PMID: 24223174

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Project description:BackgroundThe disease-associated non-coding variants identified by genome-wide association studies (GWASs) were enriched in open chromatin regions (OCRs) and implicated in gene regulation. Genetic variants in OCRs thus may exert regulatory functions and contribute to non-small cell lung cancer (NSCLC) susceptibility.ObjectiveTo fine map potential functional variants in GWAS loci that contribute to NSCLC predisposition using chromatin accessibility and histone modification data and explore their functions by population study and biochemical experimental analyses.MethodsWe mapped the chromatin accessible regions of lung tissues using data of assay for transposase-accessible chromatin using sequencing (ATAC-seq) in The Cancer Genome Atlas (TCGA) and prioritized potential regulatory variants within lung cancer GWAS loci by aligning with histone signatures using data of chromatin immunoprecipitation assays followed by sequencing (ChIP-seq) in the Encyclopedia of DNA Elements (ENCODE). A two-stage case-control study with 1,830 cases and 2,001 controls was conducted to explore the associations between candidate variants and NSCLC risk in Chinese population. Bioinformatic annotations and biochemical experiments were performed to further reveal the potential functions of significant variants.ResultsSixteen potential functional single-nucleotide polymorphisms (SNPs) were selected as candidates from bioinformatics analyses. Three variants out of the 16 candidate SNPs survived after genotyping in stage 1 case-control study, and only the results of SNP rs13064999 were successfully validated in the analyses of stage 2 case-control study. In combined analyses, rs13064999 was significantly associated with NSCLC risk [additive model; odds ratio (OR) = 1.17; 95%CI, 1.07-1.29; p = 0.001]. Functional annotations indicated its potential enhancer bioactivity, and dual-luciferase reporter assays revealed a significant increase in luciferase activity for the reconstructed plasmid with rs13064999 A allele, when compared to the one with wild-type G allele (pA549 < 0.001, pSK-MES-1 = 0.004). Further electrophoretic mobility shift assays (EMSA) and super-shift assays confirmed a stronger affinity of HP1γ for the binding motif containing SNP rs13064999 A allele.ConclusionThese findings suggested that the functional variant rs13064999, identified by the integration of ATAC-seq and ChIP-seq data, contributes to the susceptibility of NSCLC by affecting HP1γ binding, while the exact biological mechanism awaits further exploration.

Dataset Information

A genetic polymorphism in pre-miR-27a confers clinical outcome of non-small cell lung cancer in a Chinese population.

Publications

A genetic polymorphism in pre-miR-27a confers clinical outcome of non-small cell lung cancer in a Chinese population.

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