Bartsch H, Hietanen E
Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Environ Health Perspect. 1996 May;104 Suppl 3(Suppl 3):569-77. doi: 10.1289/ehp.96104s3569.
Individual susceptibility to cancer may result from host factors including differences n metabolism, DNA repair, altered expression of protooncogenes and tumor suppressor genes, and nutritional status. Since most carcinogens require metabolic activation before binding to DNA, variations in an individual's metabolic phenotype that have detected in enzymes involved in activation and detoxification should play an essential role in the development of environmental cancer. This phenotypic metabolic variation has now been related to genetic polymorphisms, and many genes encoding carcinogen-metabolizing enzymes have been identified and cloned. Consequently, allelic variants or genetic defects that give rise to the observed variation and new polymorphisms have been recognized. Development of simple polymerase chain reaction (PCR)-based assays has enabled identification of an individual's genotype for a variety of metabolic polymorphisms. Thus, recent knowledge of the genetic basis for individual metabolic variation has opened new possibilities of studies focusing on increased individual susceptibility to environmentally induced cancer, which are reviewed with special reference to smoking-induced lung cancer. Cancer susceptibility due to chemical exposure is likely to be determined by an individual's phenotype for a number of enzymes (both activating and detoxifying) relevant to that of a single carcinogen or mixtures of carcinogens. Given the number and variability in expression of carcinogen-metabolizing enzymes and the complexity of chemical exposures, assessment of a single polymorphic enzyme (genotype) may not be sufficient. Mutations in the p53 gene are among the most common genetic changes in human cancer. The frequency and type p53 mutations can act as a fingerprint of carcinogen exposure and may therefore provide information about external etiological agents, intensity of exposure, and host factors affecting the tumorigenesis process. In human lung cancer, p53 mutations (both the mutation pattern and frequency) have been linked with tobacco smoking; the type of mutation most frequently observed is G:C to T:A transversion, a mutation preferentially induced by benzo[a]pyrene diol epoxide. An association between the presence of this transversion and the genotype deficient in glutathione S-transferase M1-mediated detoxification has been observed in lung cancer. Taken together, these findings suggest that determination of metabolic at risk genotypes in combination with levels of DNA adducts in target (surrogate) tissues and the p53 mutation pattern should allow the identification of susceptible individuals and subgroups in carcinogen-exposed populations.
个体对癌症的易感性可能源于宿主因素，包括代谢差异、DNA修复、原癌基因和肿瘤抑制基因表达改变以及营养状况。由于大多数致癌物在与DNA结合之前需要代谢激活，因此在参与激活和解毒的酶中检测到的个体代谢表型差异在环境性癌症的发生发展中应起重要作用。这种表型代谢差异现在已与基因多态性相关，并且许多编码致癌物代谢酶的基因已被鉴定和克隆。因此，已识别出导致观察到的变异和新多态性的等位基因变体或遗传缺陷。基于简单聚合酶链反应（PCR）的检测方法的发展使得能够鉴定个体对于多种代谢多态性的基因型。因此，关于个体代谢变异遗传基础的最新知识为关注个体对环境诱导癌症易感性增加的研究开辟了新的可能性，本文将特别参考吸烟诱导的肺癌对此进行综述。由于化学暴露导致的癌症易感性可能由个体对于与单一致癌物或致癌物混合物相关的多种酶（包括激活酶和解毒酶）的表型决定。鉴于致癌物代谢酶表达的数量和变异性以及化学暴露的复杂性，评估单一多态性酶（基因型）可能并不足够。p53基因的突变是人类癌症中最常见的基因变化之一。p53突变的频率和类型可作为致癌物暴露的指纹，因此可能提供有关外部病因、暴露强度以及影响肿瘤发生过程的宿主因素的信息。在人类肺癌中，p53突变（包括突变模式和频率）与吸烟有关；最常观察到的突变类型是G:C到T:A颠换，这是一种优先由苯并[a]芘二醇环氧化物诱导的突变。在肺癌中已观察到这种颠换的存在与谷胱甘肽S-转移酶M1介导的解毒缺陷基因型之间的关联。综上所述，这些发现表明，结合靶（替代）组织中的DNA加合物水平和p53突变模式来确定有风险的代谢基因型，应该能够识别致癌物暴露人群中的易感个体和亚组。
