Benzo(a)pyrene diol epoxide-induced chromosome 9p21 aberrations are associated with increased risk of bladder cancer
Benzo(a)pyrene diol epoxide-induced chromosome 9p21 aberrations are associated with increased risk of bladder cancer
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DOI：
10.1158/1055-9965.epi-07-2890
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发表时间：
2008-09-01
影响因子：
3.8
通讯作者：
Wu, Xifeng
中科院分区：
文献类型：
--
作者：
Gu, Jian;Horikawa, Yohei;Wu, Xifeng
目的：染色体9 p21缺失是膀胱癌中最常见的基因组改变之一。9 p21和p16的改变也经常出现在慢性吸烟者的上皮细胞中。我们假设9 p21是烟草致癌物苯并（a）芘代谢产物苯并（a）芘二醇环氧化物（BPDE）的分子靶点，9 p21 BPDE敏感性是膀胱癌的遗传易感因素。材料和方法：在203例膀胱癌病例和198例匹配的健康对照的病例对照研究中，我们比较了使用荧光原位杂交在培养的外周血淋巴细胞中BPDE诱导的9 p21畸变的频率，并评估了9 p21 BPDE敏感性和膀胱癌风险之间的关联。结果如下：我们发现膀胱癌患者外周血淋巴细胞中BPDE诱导的染色体9 p21畸变（20.76 ± 6.97/1000）显著高于对照组（16.58 ± 7.07/1000; P < 0.0001）。然而，没有观察到差异CEP 9，9号染色体上的控制着丝粒位点。使用对照组的中位畸变值作为BPDE敏感性二分的分界点，经年龄、性别、种族和吸烟状况校正后，9 p21 BPDE敏感性与膀胱癌风险显著增加相关（优势比，5.29; 95%置信区间，3.26-8.59），而CEP 9基因座的优势比为0.99（95%置信区间，0.66-1.50）。9 p21 BPDE敏感性与膀胱癌风险增加之间也存在剂量-反应关系。结论：9 p21可能是膀胱癌BPDE损伤的分子靶点，9 p21 BPDE敏感性可能是膀胱癌易感性的标志。
Purpose: Loss of chromosome 9p21 is one of the most frequent genomic alterations in bladder cancer. Alterations of 9p21 and p16 are also frequently seen in the epithelial cells of chronic smokers. We hypothesize that 9p21 is a molecular target of benzo(a)pyrene diol epoxide (BPDE), the metabolic product of tobacco carcinogen benzo(a)pyrene, and 9p21 BPDE sensitivity is a genetic susceptibility factor for bladder cancer. Material and Methods: In this case-control study of 203 bladder cancer cases and 198 matched healthy controls, we compared the frequencies of BPDE-induced 9p21 aberrations in cultured peripheral blood lymphocytes using fluorescent in situ hybridization and evaluated the association between 9p21 BPDE sensitivity and bladder cancer risk. Results: We found that BPDE-induced chromosome 9p21 aberrations were significantly higher in peripheral blood lymphocytes of bladder cancer cases (20.76 +/- 6.97 per 1,000) than those of controls (16.58 +/- 7.07 per 1,000; P < 0.0001). However, no difference was observed for CEP9, a control centromere locus on chromosome 9. Using the median aberration value in the controls as a cutoff point to dichotomize BPDE sensitivity and after adjustment by age, sex, ethnicity, and smoking status, 9p21 BPDE sensitivity was associated with a significantly increased risk of bladder cancer (odds ratio, 5.29; 95% confidence interval, 3.26-8.59), whereas the odds ratio for the CEP9 locus was 0.99 (95% confidence interval, 0.66-1.50). There was also a dose-response relationship between the 9p21 BPDE sensitivity and increased risk for bladder cancer. Conclusion: 9p21 may be a molecular target for BPDE damage in bladder cancer cases and 9p21 BPDE sensitivity may be a marker of bladder cancer susceptibility.