Povey Andrew C, Margison Geoffrey P, Santibáñez-Koref Mauro F
Centre for Occupational and Environmental Health, University of Manchester, United Kingdom.
DNA Repair (Amst). 2007 Aug 1;6(8):1134-44. doi: 10.1016/j.dnarep.2007.03.022. Epub 2007 Jun 13.
O(6)-Alkylguanine-DNA alkyltransferase (MGMT) repairs DNA adducts that result from alkylation at the O(6) position of guanine. These lesions are mutagenic and toxic and can be produced by a variety of agents including the tobacco-specific nitrosamines, carcinogens present in cigarette smoke. Here, we review some of our work in the context of inter-individual differences in MGMT expression and their potential influence on lung cancer risk. In humans there are marked inter-individual differences in not only levels of DNA damage in the lung (N7-methylguanine) that can arise from exposure to methylating agents but also in MGMT activity in lung tissues. In the presence of such exposure, this variability in MGMT activity may alter cancer susceptibility, particularly as animal models have demonstrated that the complete absence of MGMT activity predisposes to alkylating-agent induced cancer while overexpression is protective. Recent studies have uncovered a series of polymorphisms that affect protein activity or are associated with differences in expression levels. The associations between these (and other) polymorphisms and cancer risk are inconsistent, possibly because of small sample sizes and inter-study differences in lung cancer histology. We have recently analysed a consecutive series of case-control studies and found evidence that lung cancer risk was lower in subjects with the R178 allele.
O(6)-烷基鸟嘌呤-DNA烷基转移酶（MGMT）可修复因鸟嘌呤O(6)位烷基化而产生的DNA加合物。这些损伤具有致突变性和毒性，可由多种因素产生，包括烟草特有的亚硝胺，即香烟烟雾中的致癌物。在此，我们结合MGMT表达的个体差异及其对肺癌风险的潜在影响，回顾我们的一些研究工作。在人类中，不仅因接触甲基化剂而导致的肺部DNA损伤水平（N7-甲基鸟嘌呤）存在显著的个体差异，而且肺组织中的MGMT活性也存在个体差异。在这种接触的情况下，MGMT活性的这种变异性可能会改变癌症易感性，特别是因为动物模型已经证明，完全缺乏MGMT活性会使机体易患烷基化剂诱导的癌症，而过度表达则具有保护作用。最近的研究发现了一系列影响蛋白质活性或与表达水平差异相关的多态性。这些（以及其他）多态性与癌症风险之间的关联并不一致，可能是因为样本量小以及肺癌组织学研究之间存在差异。我们最近分析了一系列连续的病例对照研究，发现有证据表明携带R178等位基因的受试者患肺癌的风险较低。
