The Polymorphism and Haplotypes of PIN1 Gene are Associated with the Risk of Lung Cancer in Southern and Eastern Chinese Populations
The Polymorphism and Haplotypes of PIN1 Gene are Associated with the Risk of Lung Cancer in Southern and Eastern Chinese Populations
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PIN1基因多态性和单倍型与中国南部和东部人群肺癌风险相关
DOI：
10.1002/humu.21574
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发表时间：
2011-11-01
期刊：
影响因子：
3.9
通讯作者：
Zhou, Yifeng
中科院分区：
文献类型：
--
作者：
Lu, Jiachun;Yang, Lei;Zhou, Yifeng
肽基-脯氨酰顺/反式异构酶(PPIase)PIN1被发现是参与多种致癌信号通路的关键催化剂。最近，PIN1基因的几个可能的功能多态被发现与癌症风险有关。在这项研究中，我们验证了Pin1启动子中两个常见的多态性c.-842G>；C(Rs2233678)和c.-667C>；T(Rs2233679)与肺癌风险相关的假设。在华南和华东地区1,559例肺癌病例和1,679例对照的两个独立病例对照研究中，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)的携带者患肺癌的风险降低(优势比[OR]=0.63，95%可信区间[CI]=0.51-0.78，p=1.13×10(-5))。虽然未发现c.-667C>；T基因多态与癌症风险相关，但我们发现单倍型“C-C”具有更大的保护作用(OR=0.39，95%CI=0.23-0.67，p=5.03×10(-4))。分层分析显示，c.-842C变异在当前吸烟者(p=4.45x10(-5))中的保护作用更为明显，尤其是在男性吸烟者(p=6.71x10(-6))和吸烟20年以上者(p=2.30x10(-5))中，c.-842C变异基因与吸烟状况(P(交互作用)=0.019)或吸烟(P(交互作用)=0.008)在降低癌症风险方面存在交互作用。进一步的功能分析表明，c.-842C突变等位基因在荧光素酶实验中转录活性较低，与核蛋白的DNA结合能力较低，在Western印迹实验中转录活性较低。总之，我们的数据表明，Pin1启动子中的功能性c.842C变异和单倍型C-C通过降低启动子活性而降低了肺癌的风险，这可能是肺癌的易感生物标志物。Hum Mutat 32：1299-1308,2011。(C)2011年威利期刊公司。
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 x 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 x 10(-4)). The stratification analysis showed that the protective role of c.-842C variants was more pronounced in current smokers (p = 4.45 x 10(-5)), especially in male smokers (p = 6.71 x 10(-6)) and in those who smoked more than 20 pack-years (p = 2.30 x 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. Hum Mutat 32: 1299-1308, 2011. (C) 2011 Wiley Periodicals, Inc.