A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25
A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25
复制标题
DOI：
10.1038/nature06885
复制
发表时间：
2008-04-03
期刊：
影响因子：
64.8
通讯作者：
Brennan, Paul
中科院分区：
文献类型：
--
作者：
Hung, Rayjean J.;Mckay, James D.;Brennan, Paul
肺癌是全世界最常见的癌症死亡原因，每年有超过100万例(1)。为了确定改变疾病风险的遗传因素，我们进行了一项全基因组关联研究，分析了来自六个中欧国家的1989例肺癌病例和2625例对照的317,139个单核苷酸多态性。我们在染色体15q25区域发现了一个与肺癌密切相关的位点（P= 9 x 10(-10)）。该基因座在另外的2513例肺癌病例和4752例对照（总体P = 5 × 10(-20)）的5项独立肺癌研究中得到了重复，发现它占肺癌病例的14%（归因风险）。无论吸烟状况或吸烟倾向如何，均观察到统计学上相似的风险。该关联区包含多个基因，包括三个编码烟碱乙酰胆碱受体亚基的基因（CHRNA5、CHRNA3和CHRNB4）。这些亚基在神经元和其他组织中表达，特别是肺泡上皮细胞、肺神经内分泌细胞和肺癌细胞系（2,3），它们与N'-亚硝基索烟碱和潜在的肺癌致癌物结合(4)。CHRNA5的一种非同义变体，在该蛋白的第二胞内环高度保守的位点诱导氨基酸替换（D398N），是与疾病关联最强的标记之一。我们的研究结果提供了令人信服的证据，证明15q25位点易患肺癌，并加强了对烟碱乙酰胆碱受体作为潜在疾病候选者和化学预防靶点的兴趣(5)。
Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually(1). To identify genetic factors that modify disease risk, we conducted a genome- wide association study by analysing 317,139 single- nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer ( P= 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls ( P = 5 x 10(-20) overall), and it was found to account for 14%( attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits ( CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines(2,3), and they bind to N'- nitrosonornicotine and potential lung carcinogens(4). A non- synonymous variant of CHRNA5 that induces an amino acid substitution ( D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets(5).