前列腺癌抗原3基因启动子短片段重复序列多态性与前列腺癌发生风险的关系

Association of polymorphism in the promoter region of PCA3 gene with risk of prosate cancer

目的：分析前列腺癌抗原3（ PCA3）基因启动子序列的多态性改变，及其与前列腺癌（PCa）发生风险的关系。方法提取186例PCa患者、141例前列腺增生（BPH）患者和135例健康体检者外周血单个核细胞的DNA，采用多聚酶链式反应扩增PCA3基因的启动子片段后进行克隆测序分析。结果 PCA3基因的启动子序列因插入TAAA重复次数不同而形成短片段重复序列（ STR）多态性。除了检测到GenBank公布的PCA3基因启动子序列含TAAA的5次重复外，还检测到4种新的启动子序列，分别含TAAA的重复次数为4、6、7、8，共组成TAAA 4／5型、TAAA 4／6型、TAAA 5／5型、TAAA 5／6型、TAAA 5／7型、TAAA 5／8型、TAAA 6／6型和TAAA 6／7型等8种类型。根据PCA3基因启动子等位基因上 TAAA总重复次数的不同，将8种组合类型分成≤10TAAA、11TAAA 和≥12TAAA等3组。非条件Logistic回归分析显示，校正性别和年龄因素后，随着PCA3基因启动子上TAAA总重复次数的增加，相对于≤10TAAA组，11TAAA组（ ORadj ＝1．74，95％CI为1．06～2．87， P＜0．05）和≥12TAAA组（ORadj ＝5．63，95％ CI为1．85～17．19， P＜0．05）的PCa发生风险有增高趋势，而发生BPH的风险不变（均P＞0．05）。在186例PCa患者中，共有62．4％的PCA3等位基因在启动子的18～19 bp处发现存在AG／CA突变。结论 PCa患者PCA3基因的启动子存在STR多态性改变，TAAA重复序列的增加使患者发生PCa的相对危险度大大增加，而这种STR的发生可能与其上游位点突变有关。

Objective To investigate the polymorphism in the promoter region of PCA3 gene and its relationship with risk of prostate cancer （ PCa） . Methods The promoter region of PCA3 gene of the DNA of peripheral blood mononuclear cells was detected by sequence analysis in the 186 PCa and 141 BPH patients and 135 healthy control individuals. If the samples were detected with polymorphism of insection/deletion, clone sequence analysis was used with pBS-T carrier to verify it. Results There were 5 polymorphisms. TAAA repeat times：4, 5, 6, 7, 8, and 8 genotypes （TAAA 4/5, TAAA 4/6, TAAA 5/5, TAAA 5/6, TAAA 5/7, TAAA 5/8, TAAA 6/6, and TAAA 6/7） were detected in the promoter region of PCA3 gene. The eight genotypes were divided into three groups： ≤10TAAA, 11TAAA, ≥12TAAA. Unconditional logistic regression analysis models were used to analyze the relationship between different genotypes and cancer risks adjusted by sex and age. The type 11TAAA and≥12TAAA was associated with higher relative risk for prostate cancer than the group ≤10TAAA [ OR=1. 74, 95%CI=1. 06-2. 87 （ for type 11TAAA）;OR=5. 63, 95%CI=1. 85-17. 19 （for type≥12TAAA）]. In the 186 PCa patients, there was 62. 4% allele of PCA3 gene with AG/CA mutation found in the promoter 18-19 bp region of PCA3 gene and it had a close relation with the development of prostate cancer. Conclusions Short tandem repeats are found in the promoter region of the PCA3 gene in PCa patients, and the increase of TAAA repeat sequences highly enhance the relative risk of prostate cancer development. The occurrence of such STR might be related to the mutations in their upstream loci.