Hum Mutat 2011 Nov;32 (11): 1299-308. [IF:5.956]
The polymorphism and haplotypes of PIN1 gene are associated with the risk of lung cancer in Southern and Eastern Chinese populations.
Lu J , Yang L , Zhao H , Liu B , Li Y , Wu H , Li Q , Zeng B , Wang Y , Ji W , Zhou Y .
The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, PR China. jcLu@gzhmc.edu.cn
广州医学院化学致癌研究所，呼吸疾病国家重点实验室
Abstract
Peptidyl-prolyl cis/trans isomerase (PPIase), PIN1, has been found to be a critical catalyst that involves in multiple oncogenic signaling pathways. Recently, several putative functional polymorphisms of the PIN1 gene have been identified to be associated with cancer risk. In this study, we tested the hypothesis that two common polymorphisms, c.-842G>C (rs2233678) and c.-667C>T (rs2233679), in the PIN1 promoter are associated with risk of lung cancer. In two independent case-control studies of 1,559 lung cancer cases and 1,679 controls conducted in Southern and Eastern Chinese population, we found that compared with the most common c.-842GG genotype, the carriers of c.-842C variant genotypes (GC + CC) had a decreased risk of lung cancer (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.51-0.78, p = 1.13 × 10(-5) ). Although no association was observed between the c.-667C>T polymorphism and cancer risk, we found that the haplotype "C-C" had a greater protective effect (OR = 0.39, 95% CI = 0.23-0.67, p = 5.03 × 10(-4) ). The stratification analysis showed that the protective role of c.-842C variants was more pronounced in current smokers (p = 4.45 × 10(-5) ), especially in male smokers (p = 6.71 × 10(-6) ) and in those who smoked more than 20 pack-years (p = 2.30 × 10(-5) ) and the c.-842C variant genotypes interacted with smoking status (P(interaction) = 0.019) or pack-years smoked (P(interaction) = 0.008) on reducing cancer risk. Further functional assay revealed that the c.-842C variant allele had a lower transcription activity in luciferase assay and a lower DNA-binding ability with nuclear proteins, and low transcription activity in western blot assay. In conclusions, our data suggest that functional c.-842C variants and haplotype "C-C" in the PIN1 promoter contribute to decreased risk of lung cancer by diminishing the promoter activity, which may be susceptibility biomarkers for lung cancer.
摘要
肽基脯氨酰顺/反异构酶（PPIase），PIN1，已被发现是一个涉及多种致癌信号通路的关键催化剂。最近，一些研究认为PIN1基因变异与癌症风险有关。在本项研究中，我们研究了PIN1基因变异与肺癌危险因素的相关性，研究包括两种常见的基因变异，C. - 842G> C（rs2233678）和C. - 667C> T（rs2233679）。研究包括两个独立的病例对照研究，涉及在中国南部和东部人口中的1559例肺癌病例及1679例对照病例。我们发现，与最常见的C - 842GG基因型相比，C.- 842C变异基因型（GC + CC）携带者患肺癌的风险降低（相对危险度OR = 0.63，95％的可信区间[CI] = 0.51-0.78，P = 1.13 × 10（-5））。虽然没有观察到C.- 667C>T基因变异与癌症风险之间的关联，我们发现，“C-C”的单体型基因有明显的保护作用（OR = 0.39，95％CI = 0.23-0.67，P = 5.03 × 10（ -4））。分层分析表明，C.-842C基因变异具有保护作用，其降低肺癌患病风险在目前仍然吸烟者中更明显（p= 4.45 × 10（-5）），尤其是在男性吸烟者中（P = 6.71 × 10（-6））和那些吸烟超过20包/年者（P = 2.30 × 10（-5））和C. - 842C变异基因型与吸烟状态交互作用（P（交互）= 0.019）或按年-包分级者中（P（交互）=0.008）。进一步的功能试验显示，C.-842C变异等位基因在荧光素酶检测的转录活性较低，具有较低的与核蛋白DNA结合能力，Western blot分析也显示了其具有低转录活性。总之，我们的研究表明，C.-842C基因变异和单体型“CC”可以通过降低PIN1启动子转录活性而降低了肺癌患病风险，其可能是肺癌易感性的生物标志物。
