The p53 codon 72 polymorphism and lung cancer risk.
The p53 codon 72 polymorphism and lung cancer risk.
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发表时间：
2000-10
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通讯作者：
R. Fan;M. Wu;D. Miller;J. Wain;K. Kelsey;J. Wiencke;D. Christiani
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作者：
R. Fan;M. Wu;D. Miller;J. Wain;K. Kelsey;J. Wiencke;D. Christiani
p53肿瘤抑制基因在许多形式的人类癌症中经常发生突变。常见的多态性发生在第4号外显子密码子72处，有两个等位基因编码精氨酸（CGC）或脯氨酸（CCC）。据报道，这种p53多态性与肺癌易感性有关。然而，并不是所有的研究都是一致的，这种假设的联系仍然存在争议。我们在一项大型肺癌病例对照研究中检验了Pro/Pro基因型与肺癌风险增加相关的假设，该研究包括来自马萨诸塞州波士顿的马萨诸塞州总医院的482例病例和510例对照。外周血标本采用PCR-RFLP检测DNA。Pro/Pro纯合子在腺癌中更为常见（病例为16.4%，对照组为12.0%,P = 0.03）。Pro/Pro纯合基因型的患病率随着吸烟包年的增加而增加。经相关变量校正后，纯合子Pro/Pro和杂合子Arg/Pro联合易感基因型与Arg/Arg基因型相比，腺癌风险高1.45倍（95%置信区间= 1.01-2.06;P = 0.04）。肺腺癌的风险随着吸烟人群中一个或两个变异等位基因的存在而增加。此外，在每个吸烟水平（不吸烟者和轻度吸烟者除外），具有组合变异（Arg/Pro + Pro/Pro）基因型的人群与吸烟相关的风险更高。合并基因型的风险与烟草暴露状况有关。综上所述，常见抑癌基因p53的密码子72种系多态性（Arg/Pro）与烟雾诱导肺腺癌的遗传易感性有关。p53多态性和包年的改变导致易感基因型患肺腺癌的风险增加。p53基因可能调节对环境致癌物的反应，从而影响肺腺癌的发生风险。
The p53 tumor suppressor gene frequently is mutated in many forms of human carcinomas. A common polymorphism occurs at codon 72 of exon 4, with two alleles encoding either arginine (CGC) or proline (CCC). This p53 polymorphism reportedly is associated with lung cancer susceptibility. However, not all investigations have been consistent, and this hypothesized association remains controversial. We tested the hypothesis that the Pro/Pro genotype is associated with increased lung cancer risk in a large case-control study of lung cancer that included 482 cases and 510 controls from the Massachusetts General Hospital in Boston, Massachusetts. DNA from peripheral blood samples was examined by PCR-RFLP. Pro/Pro homozygotes were found more frequently in adenocarcinomas (cases, 16.4%; controls, 12.0%; P = 0.03). The prevalence of the Pro/Pro homozygous genotype increased in frequency with increasing pack-years of smoking. The combined susceptible genotype homozygous Pro/Pro and heterozygous Arg/Pro was associated with a 1.45-fold higher risk of adenocarcinoma compared with Arg/Arg genotype (95% confidence interval = 1.01-2.06; P = 0.04) after adjustment for relevant variables. Lung adenocarcinoma risk increased with the presence of one or both variant alleles across smoking strata. In addition, at each level of smoking (except nonsmoker and light smoker), the risk associated with smoking was higher for the population with the combined variant (Arg/Pro + Pro/Pro) genotype. The risk for the combined genotype was associated with tobacco exposure status. In conclusion, the codon 72 germ-line polymorphism (Arg/Pro) of the common tumor suppressor gene p53 contributes to heritable susceptibility for smoke-induced lung adenocarcinoma. The modifications by p53 polymorphism and pack-years resulted in an increased risk of the susceptible genotype to lung adenocarcinoma. The p53 gene may modulate the response to environment carcinogens and thereby affect the risk of developing lung adenocarcinoma.