Liu Lin, Qiu Fuman, Chen Jiansong, Wu Di, Nong Qingqing, Zhou Yifeng, Lu Jiachun
The State Key Laboratory of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, 151 Yanjiangxi Road, Guangzhou, 510120, China.
The School of Public Health, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou, 510182, China.
Curr Genomics. 2018 Aug;19(5):375-383. doi: 10.2174/1389202919666171128151544.
Musashi1 (MSI1) is a characteristic stem cell marker that regulates the balance between cell self-renewal and differentiation. Evidence has identified MSI1 as a pivotal oncogenic regulator in diverse malignancies. However, little evidence uncovers the role of genetic variations of MSI1 gene in cancer etiology.
The aim of this study was to investigate the association between genetic variants in the MSI1 gene and lung cancer risk.
Based on a two-stage retrospective study with a total of 1559 patients with lung cancer and 1667 healthy controls, we evaluated the relevance between three putative functional SNPs in the MSI1 promoter (i.e., -2696T>C[rs7959801], -2297T>C[rs3742038] and -1081C>T[rs34570155]) and lung cancer risk.
We found that the SNP rs7959801T>C was significantly associated with lung cancer susceptibility. Compared to those with rs7959801TT wild-genotype, individuals with CT/CC variant genotypes exerted consistently beneficial roles in lung cancer risk in the discovery set (adjusted odd ratios [OR] = 0.67; 95% confidence interval [CI] = 0.57-0.80), and in the validation set (OR=0.69; 95%CI=0.54-0.88). Functional assays indicated that the allele transformation from T to C in rs7959801 of MSI1 gene arrestingly decreased its transcription activity in vitro. Furthermore, the expression levels of MSI1 were significantly lower in the patients with CT/CC variants than in those who were with TT genotype.
Our findings suggested that the rs7959801T>C polymorphism in the MSI1 promoter conferred a decreased risk to lung cancer by reducing the expression of MSI1 and it may be a promising indicator for lung cancer predisposition.
Musashi1（MSI1）是一种特征性的干细胞标志物，可调节细胞自我更新与分化之间的平衡。有证据表明MSI1是多种恶性肿瘤中关键的致癌调节因子。然而，几乎没有证据揭示MSI1基因的遗传变异在癌症病因学中的作用。
本研究旨在探讨MSI1基因的遗传变异与肺癌风险之间的关联。
基于一项两阶段的回顾性研究，共纳入1559例肺癌患者和1667例健康对照，我们评估了MSI1启动子中三个假定的功能性单核苷酸多态性（即-2696T>C[rs7959801]、-2297T>C[rs3742038]和-1081C>T[rs34570155]）与肺癌风险的相关性。
我们发现单核苷酸多态性rs7959801T>C与肺癌易感性显著相关。与rs7959801TT野生基因型个体相比，CT/CC变异基因型个体在发现组（校正比值比[OR]=0.67；95%置信区间[CI]=0.57-0.80）和验证组（OR=0.69；95%CI=0.54-0.88）中对肺癌风险始终具有有益作用。功能分析表明，MSI1基因rs7959801位点的等位基因从T转变为C在体外显著降低了其转录活性。此外，CT/CC变异患者中MSI1的表达水平显著低于TT基因型患者。
我们的研究结果表明，MSI1启动子中的rs7959801T>C多态性通过降低MSI1的表达降低了肺癌风险，它可能是肺癌易感性的一个有前景的指标。
