Functional Studies of Candidate Lung Cancer Susceptibility Genes

项目总结(见说明)： 作为已经完成的GWAS研究的结果，已经确定了用于进一步功能表征的突出的基因座。特别是，正如下面更详细描述的那样，烟碱型乙酰胆碱受体单元5(CHRNAS)中的rs1696698 SNP影响肺癌的风险，影响吸烟行为，并已被证明在体外影响多聚体烟碱受体的活性。虽然该变异对尼古丁受体活性有重要影响，但在高加索人和非裔美国人中的广泛研究表明，它并不是染色体15q24-25.1区域唯一影响肺癌风险和吸烟行为的变异，而且RSL 696698的影响仍然缺乏特征性。因此，我们计划进行进一步的研究，以确定该区域变异对烟碱受体活性的影响，该区域基因的表达，以及变异对与癌症发展相关的细胞表型的影响。 和进步。此外，Gwas的研究已经确定了染色体5p和6p上的优秀候选基因，需要进一步的详细分析。对于区域2的目标1，我们建议对已确定的基因座的甲基化进行表征。我们还建议对已确定的基因座和现有动物模型中的表型进行额外的基于细胞表型的分析。区域2的目的2将确定CHRNA3/CHRNA5基因多态性对神经元型烟碱型乙酰胆碱受体(NAChRs)生物物理和药理学特性的影响。我们还建议对已确定的基因座进行额外的基于细胞表型的分析，并评估现有和新的动物模型中的表型(区域2的目标3和4)。

PROJECT SUMMARY (See instmctions): As a result of the already complete GWAS studies, outstanding loci for further functional characterization have already been identified. In particular, and as described in more detail below, the rs1696698 SNP in the nicotinic acetycholine receptor unit 5 (CHRNAS) influences risk for lung cancer and affects smoking behavior and has also been shown to affect the activity of the multimeric nicotinic receptor in vitro. While this variant has important effects on nicotine receptor activity, extensive studies in Caucasian and African-American populations show that it is not the only variant influencing lung cancer risk and smoking behavior in the region of chromosomes 15q24-25.1, and the effects of rsl 696698 remain poorly characterized. Therefore, we plan further studies to define effects of variations in this region on nicotinic receptor activity, expression of the genes in the region and on effects of variations on cellular phenotypes relating to cancer development and progression. In addition, GWAS studies have identified excellent candidates on chromosomes 5p and 6p that wanrant further detailed analyses. For aim 1 of area 2 we propose to characterize methylation for the loci that have been identified. We also propose additional cellular phenotype based assays for loci that have been identified and the evaluation of phenotypes in existing animal models. Aim 2 of area 2 will detemiine the effect of CHRNA3/CHRNA5 polymorphisms on the biophysical and pharmacological properties of neuronal nicotinic acetylcholine receptors (nAChRs). We also propose additional cellular phenotype based assays for loci that have been identified and the evaluation of phenotypes in existing and new animal models (Aims 3 & 4 of area 2)..