The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, People's Republic of China.
Int J Cancer. 2012 Sep 1;131(5):E744-58. doi: 10.1002/ijc.27407. Epub 2012 Feb 18.
Human proto-oncogene c-Jun and c-Fos assemble the activator protein-1 complex which is a crucial transcription factor responding to environmental factors and promotes tumorgenesis. We hypothesized that genetic variants in these two genes may alter the carriers' susceptibility to lung cancer. In two independent case-control studies, we genotyped three putative functional polymorphisms (-1318T>G and -673T>C of c-Jun; -60C>T of c-Fos) in southern Chinese and then validated the association in eastern Chinese. We found that compared to -1318TT genotype, the -1318GT/GG variant genotypes had an increased lung cancer risk (OR=1.46, 95% CI=1.26-1.69), and the -673CC genotype had an increased lung cancer risk compared to -673TT/CT genotypes (OR=1.35, 95% CI=1.17-1.56) in the total 1,559 cases versus 1,679 controls. After combining these two loci, the number of the risk genotypes was associated with increased cancer risk in a dose-response manner (ptrend=2.21×10(-11)); moreover, the risk genotypes interacted with smoking or drinking status on increasing cancer risk (p values of interaction were 0.009 and 0.007, respectively). Further, we found that those with -1318GT/GG genotypes, -673CC genotypes or both genotypes in c-Jun had higher mRNA and protein expression levels in vivo, and those variants had higher transcription activities in reporter genes in vitro, especially under the stimuli with tobacco extract or alcohol mixture as luciferase assay shown. However, for -60C>T of c-Fos, no significant association was observed for lung cancer risk. Our data suggested that the genetic variants in c-Jun (-1318T>G and -673T>C) increase the carriers' susceptibility to lung cancer via interaction with smoking or drinking on increasing the c-Jun's expression.
人类原癌基因 c-Jun 和 c-Fos 组装激活蛋白-1 复合物，这是一种关键的转录因子，对环境因素作出反应，并促进肿瘤发生。我们假设这两个基因的遗传变异可能会改变携带者患肺癌的易感性。在两项独立的病例对照研究中，我们对中国南方人群中的三个假定功能性多态性（c-Jun 的-1318T>G 和-673T>C；c-Fos 的-60C>T）进行了基因分型，然后在中国东部进行了验证。我们发现，与-1318TT 基因型相比，-1318GT/GG 变异基因型患肺癌的风险增加（OR=1.46，95%CI=1.26-1.69），与-673CC 基因型相比，-673TT/CT 基因型患肺癌的风险增加（OR=1.35，95%CI=1.17-1.56）。在总计 1559 例病例和 1679 例对照中。合并这两个位点后，风险基因型的数量与癌症风险呈剂量反应关系（ptrend=2.21×10(-11)）；此外，风险基因型与吸烟或饮酒状态相互作用增加癌症风险（交互作用的 p 值分别为 0.009 和 0.007）。此外，我们发现 c-Jun 中的-1318GT/GG 基因型、-673CC 基因型或这两种基因型的个体体内 c-Jun 的 mRNA 和蛋白表达水平更高，并且在体外报告基因中，这些变异具有更高的转录活性，特别是在以烟草提取物或酒精混合物作为萤光素酶测定的刺激物时。然而，对于 c-Fos 的-60C>T，我们没有观察到与肺癌风险相关的显著关联。我们的数据表明，c-Jun 中的遗传变异（-1318T>G 和-673T>C）通过与吸烟或饮酒相互作用增加 c-Jun 的表达，增加了携带者患肺癌的易感性。
