Xu Jiali, Tian Shengwang, Yin Zhiqiang, Wu Shuangshuang, Liu Lingxiang, Qian Yingying, Pei Dong, Gao Wen, Xu Jing, Yin Yongmei, Liu Ping, Shu Yongqian
Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of Oncology, Jintan People's Hospital Affiliated to Jiangsu University, Jintan 213200, China.
Lung Cancer. 2014 Sep;85(3):442-8. doi: 10.1016/j.lungcan.2014.06.010. Epub 2014 Jun 21.
Single-nucleotide polymorphisms (SNPs) in 3'-untranslated regions of cancer-related genes might affect regulation by microRNAs and contribute to cancer patients' outcome.
We used public databases to identify SNPs within miRNA-binding sites in deregulated genes in non-small cell lung cancer (NSCLC). A total of 13 SNPs in 10 genes were included and genotyped by SNaPshot assay in 576 NSCLC patients. Associations between SNPs, overall survival (OS) and chemotherapy response were evaluated by Cox regression and logistic regression. We then examined the functionality of the significant polymorphisms.
Two SNPs (TYMS rs2790 and MICA rs9266825) were significantly associated with OS. In the combined analysis, an increasing number of unfavorable loci was associated with a poorer prognosis (P for trend<0.001) and patients having 2-3 unfavorable loci had a 1.61-fold elevated risk of death (95% confidence interval: 1.20-2.15), compared with those carrying 0-1 unfavorable loci. A significant effect of SNPs on platinum-based chemotherapy response was observed among 296 advanced NSCLC patients without surgical operation: rs2790, rs4246215 and rs1882. Further analysis using mRNA expression data from the HapMap suggested that these significant loci (FEN1 rs4246215, HDAC2 rs11391, MICA rs1882 and rs9266825) were closely associated with host genes expression. In vitro functional study for TYMS rs2790 was carried out. Luciferase assay showed a lower expression level for rs2790 G allele as compared with A allele, and the hsa-miR-1248 had an effect on modulation of TYMS gene.
Our data indicate that miRNA-binding site SNPs in deregulated genes may serve as candidate prognostic markers of NSCLC clinical outcome.
癌症相关基因3'-非翻译区的单核苷酸多态性（SNP）可能影响微小RNA的调控，并对癌症患者的预后产生影响。
我们利用公共数据库识别非小细胞肺癌（NSCLC）中失调基因的微小RNA结合位点内的SNP。共纳入10个基因中的13个SNP，并通过SNaPshot分析对576例NSCLC患者进行基因分型。通过Cox回归和逻辑回归评估SNP、总生存期（OS）和化疗反应之间的关联。然后我们研究了显著多态性的功能。
两个SNP（TYMS rs2790和MICA rs9266825）与OS显著相关。在联合分析中，不利位点数量的增加与较差的预后相关（趋势P<0.001），与携带0-1个不利位点的患者相比，携带2-3个不利位点的患者死亡风险升高1.61倍（95%置信区间：1.20-2.15）。在296例未接受手术的晚期NSCLC患者中观察到SNP对铂类化疗反应有显著影响：rs2790、rs4246215和rs1882。使用来自HapMap的mRNA表达数据进行的进一步分析表明，这些显著位点（FEN1 rs4246215、HDAC2 rs11391、MICA rs1882和rs9266825）与宿主基因表达密切相关。对TYMS rs2790进行了体外功能研究。荧光素酶分析显示，与A等位基因相比，rs2790 G等位基因的表达水平较低，且hsa-miR-1248对TYMS基因有调节作用。
我们的数据表明，失调基因中的微小RNA结合位点SNP可能作为NSCLC临床结局的候选预后标志物。
