Genetic variation in the nucleoticle excision repair pathway and bladder cancer risk
Genetic variation in the nucleoticle excision repair pathway and bladder cancer risk
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DOI：
10.1158/1055-9965.epi-05-0749
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发表时间：
2006-03-01
影响因子：
3.8
通讯作者：
Rothman, N
中科院分区：
文献类型：
--
作者：
García-Closas, M;Malats, N;Rothman, N
核苷酸切除修复（NER）对于防止烟草烟雾中致癌物的损害至关重要。我们通过分析7个NER基因（XPC、RAD 23 B、1 RCCI、ERCC 2、ERCC 4、ERCC 5和ERCC 6）的22个单核苷酸多态性（SNP）来评估NER途径中常见遗传变异对膀胱癌风险的影响。我们的研究人群包括来自西班牙的1,150例膀胱移行细胞癌患者和1,149例对照受试者。根据年龄、性别、地区和吸烟状况调整比值比（OR）和95%置信区间（95%CI）。与具有纯合野生型基因型的受试者相比，具有所评估的七个基因中的四个中的SNP的变异基因型的受试者具有膀胱癌风险的小幅增加：（OR，1.3; 95% CI，1.1-1.5; P = 0.01），ERCC2 R156 R（OR，1.3; 95%CI，1.1-1.6; P = 0.006），ERCC1 IVS5+33A > C（OR，1.2; 95% CI，1.0-1.5; P = 0.06; P趋势= 0.04）和ERCC 5 M254 V（OR，1.4 95% CI，1.0-2.0; P = 0.04）。通路效应的全球检验表明，以本研究中分析的22个SNPs为特征的NER遗传变异显著预测膀胱癌风险（P = 0.04）。配对比较表明，携带两个基因的变异可能导致风险大幅增加。分类树分析表明，存在由吸烟和NER基因型定义的个体亚组，这些亚组可能会大幅增加风险。总之，这些发现为NER或膀胱癌风险中遗传变异的影响提供了支持。关键NER基因的遗传变异的详细表征是必要的，并可能最终有助于确定可能导致风险大幅增加的多种易感性变体。
Nucleotide excision repair (NER) is critical for protecting against damage from carcinogens in tobacco smoke. We evaluated the influence of common genetic variation in the NER pathway on bladder cancer risk by analyzing 22 single nucleotide polymorphisms (SNP) in seven NER genes (XPC, RAD23B, 1RCCI, ERCC2, ERCC4, ERCC5, and ERCC6). Our study population included 1,150 patients with transitional cell carcinoma of the urinary bladder and 1,149 control subjects from Spain. Odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, gender, region, and smoking status. Subjects with the variant genotypes for SNPs in four of the seven genes evaluated had small increases in bladder cancer risk compared to subjects with the homozygous wild-type genotypes: RAD23B IVS5-15A > G (OR, 1.3; 95% CI, 1.1-1.5; P = 0.01), ERCC2 R156R (OR, 1.3; 95% Cl, 1.1-1.6; P = 0.006), ERCC1 IVS5+33A > C (OR, 1.2; 95% CI, 1.0-1.5; P = 0.06; P-trend = 0.04), and ERCC5 M254V (OR, 1.4 95% CI, 1.0-2.0; P = 0.04). A global test for pathway effects indicated that genetic variation in NER characterized by the 22 SNPs analyzed in this study significantly predicts bladder cancer risk (P = 0.04). Pairwise comparisons suggested that carrying variants in two genes could result in substantial increases in risk. Classification tree analyses suggested the presence of subgroups of individuals defined by smoking and NER genotypes that could have substantial increases in risk. In conclusion, these findings provided support for the influence of genetic variation in NER or bladder cancer risk. A detailed characterization of genetic variation in key NER genes is warranted and might ultimately help identify multiple susceptibility variants that could be responsible for substantial joint increases in risk.