谷胱甘肽S-转移酶P1（GSTP1）、谷胱甘肽S-转移酶M1（GSTM1）和p53基因变异基因型的组合与肺癌风险增加相关。

Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk.

作者信息

Miller David P, Liu Geoffrey, De Vivo Immaculata, Lynch Thomas J, Wain John C, Su Li, Christiani David C

机构信息

Department of Environmental Heath, Occupational Health Program, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.

出版信息

Cancer Res. 2002 May 15;62(10):2819-23.

PMID:12019159

Abstract

GSTP1 and GSTM1 are genes involved in Phase II metabolism, whereas p53 is a tumor suppressor gene. Individually, functional polymorphisms of these genes have been studied as risk factors for lung cancer. Small sample sizes have hindered the detection of possible increases in risk associated with having two or more "at risk" polymorphisms of these three genes. In a large Caucasian population, we examined the association of combined variant genotypes [or double-variants (DVs)] of these three genes and lung cancer risk, compared with their corresponding "double-wild-type" genotypes. Because these DVs may promote lung carcinogenesis at an earlier age, a subgroup of individuals aged 55 years or younger was examined separately. Using a case-control design, individuals were genotyped for GSTM1, GSTP1, and p53 codon 72 using PCR-RFLP techniques. All of the analyses used multiple logistic regression. Indicator variables were created to evaluate the risk for individuals with the following DVs: GSTP1 GG + GSTM1-null and GSTP1 GG + p53 Arg/Pro or Pro/Pro. A total of 1694 cases and controls were evaluated. In the whole population, those with the double variants have a higher risk of lung cancer when compared with those with the double-wild-type genotypes, supporting our original hypothesis. Individuals with the GSTP1 and GSTM1, DV (P1-M1 DV) had a marginally significant higher risk of lung cancer compared with their double-wild-type counterparts [adjusted odds ratio (AOR), 1.60; 95% confidence interval (CI), 0.95-2.70]. A significantly higher risk was found for the GSTP1, p53 DV (P1-p53 DV; AOR, 1.99; 95% CI, 1.12-3.53). Among individuals aged 55 or younger, these risks were even higher: for the P1-M1 DV the AOR was 4.03 (95% CI, 1.47-11.1); for the P1-p53 DV the AOR was 5.10 (95% CI, 1.42-18.30). Specific DVs of GSTM1, GSTP1, and p53 codon 72 are associated with a higher lung cancer risk. This susceptibility is highest among younger individuals.

摘要

谷胱甘肽S-转移酶P1（GSTP1）和谷胱甘肽S-转移酶M1（GSTM1）是参与Ⅱ相代谢的基因，而p53是一种肿瘤抑制基因。就个体而言，这些基因的功能多态性已作为肺癌的风险因素进行了研究。小样本量阻碍了对这三个基因具有两个或更多“风险”多态性可能增加的风险的检测。在一个大型白种人群体中，我们研究了这三个基因的联合变异基因型[或双变异体（DVs）]与肺癌风险的关联，并与它们相应的“双野生型”基因型进行了比较。由于这些双变异体可能在更早的年龄促进肺癌发生，因此对55岁及以下的个体亚组进行了单独研究。采用病例对照设计，使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术对个体的GSTM1、GSTP1和p53密码子72进行基因分型。所有分析均使用多元逻辑回归。创建指示变量以评估具有以下双变异体的个体的风险：GSTP1 GG + GSTM1缺失型以及GSTP1 GG + p53 Arg/Pro或Pro/Pro。总共评估了1694例病例和对照。在整个人口中，与双野生型基因型个体相比，具有双变异体的个体患肺癌的风险更高，这支持了我们最初的假设。与双野生型对应个体相比，具有GSTP1和GSTM1双变异体（P1-M1 DV）的个体患肺癌的风险略高[调整优势比（AOR），1.60；95%置信区间（CI），0.95 - 2.70]。发现GSTP1、p53双变异体（P1-p53 DV）的风险显著更高（AOR，1.99；95% CI，1.12 - 3.53）。在55岁及以下的个体中，这些风险甚至更高：对于P1-M1 DV，AOR为4.03（95% CI，1.47 - 11.1）；对于P1-p53 DV，AOR为5.10（95% CI，1.42 - 18.30）。GSTM1、GSTP1和p53密码子72的特定双变异体与更高的肺癌风险相关。这种易感性在较年轻个体中最高。