Collins A R
Rowett Research Institute, DNA Instability Group, Bucksburn, Aberdeen, UK.
Mol Aspects Med. 1998 Dec;19(6):359-432. doi: 10.1016/s0098-2997(99)00003-5.
The use of molecular biomarkers in epidemiological investigations brings clear advantages of economy, speed and precision. Epidemiology--the study of the factors that control the patterns of incidence of disease--normally requires large numbers of subjects and/or long periods of time, because what is measured (the occurrence of disease) is a rare event. Biomarkers are measurable biological parameters that reflect, in some way, an individual's risk of disease-because they indicate exposure to a causative (or protective) agent, or because they represent an early stage in development of the disease, or because they allow an assessment of individual susceptibility. Biomarkers must be usable on one of the few materials available for biomonitoring of humans, i.e. blood, urine, exfoliated epithelial cells and, with some difficulty, biopsies. The approach of molecular epidemiology has a great potential is several areas of cancer research: investigating the aetiology of the disease; monitoring cancer risk in people exposed to occupational or environmental carcinogens; studying factors that protect from cancer; and assessing intrinsic factors that might predispose to cancer. The biomarkers most commonly employed in cancer epidemiology include: measurements of DNA damage--DNA breaks, altered bases, bulky adducts--in lymphocytes; the surrogate marker of chemical modifications to blood proteins, caused by agents that also damage DNA; the presence of metabolites of DNA-damaging agents (or the products of DNA damage themselves) in urine; chromosome alterations, including translocations, micronuclei and sister chromatid exchange, resulting from DNA damage; mutations in marker genes; DNA repair; and the differential expression of a variety of enzymes, involved in both activation and detoxification of carcinogens, that help to determine individual susceptibility. The molecular approach has been enthusiastically employed in several studies of occupational/environmental exposure to carcinogens. While the estimation of biological markers of exposure has certainly shown the expected effects in terms of DNA damage and adducts, the detection of the biological effects of exposure (e.g. at the level of chromosome alterations) has not been so clear-cut. This is true also when smokers are examined as a group compared with non-smokers. Several markers (especially of chromosome damage and mutation) show a strong correlation with age-indicating either an increasing susceptibility to damage with age, or an accumulation of long-lived changes. DNA repair--a crucial player in the removal of damage before it can cause mutation--may vary between individuals, and may be modulated by intrinsic or extrinsic factors, but limited data are available because of the lack of a reliable assay. Information on other enzymes determining individual susceptibility does exist, and some significant effects of phenotypic or genotypic polymorphisms have emerged, although the interactions between various enzymes make the situation very complex. The important question of whether oxidative DNA damage in normal cells is decreased by dietary antioxidants (vitamin C, carotenoids etc., from fruit and vegetables) has been tackled in antioxidant supplementation experiments. The use of poorly validated assays for base oxidation has not helped us to reach a definitive answer; it seems that, in any case, the level of oxidative damage has been greatly exaggerated. DNA-damaging agents lead to characteristic kinds of base changes (transitions, transversions, deletions). The investigation of the spectrum of mutations in cancer-related genes studied in tumour tissue should lead to a better understanding of the agents ultimately responsible for inducing the tumour. Similarly, studying mutations in a neutral marker gene (not involved in tumorigenesis) can tell us about the origins of the 'background' level of mutations. So far, interpretation of the growing databases is largely speculative. (ABSTRACT
在流行病学调查中使用分子生物标志物具有经济、快速和精确等明显优势。流行病学——研究控制疾病发病模式的因素——通常需要大量受试者和/或较长时间，因为所测量的（疾病的发生）是一个罕见事件。生物标志物是可测量的生物学参数，以某种方式反映个体的疾病风险，因为它们表明接触了致病（或保护）因子，或者因为它们代表疾病发展的早期阶段，或者因为它们有助于评估个体易感性。生物标志物必须能够用于可用于人体生物监测的少数几种材料之一，即血液、尿液、脱落的上皮细胞，以及活检组织（有一定难度）。分子流行病学方法在癌症研究的几个领域具有巨大潜力：调查疾病的病因；监测接触职业或环境致癌物人群的癌症风险；研究预防癌症的因素；以及评估可能易患癌症的内在因素。癌症流行病学中最常用的生物标志物包括：淋巴细胞中DNA损伤（DNA断裂、碱基改变、大的加合物）的测量；由也会损伤DNA的因子引起的血液蛋白质化学修饰的替代标志物；尿液中DNA损伤剂的代谢产物（或DNA损伤本身的产物）的存在；DNA损伤导致的染色体改变，包括易位、微核和姐妹染色单体交换；标记基因中的突变；DNA修复；以及多种参与致癌物激活和解毒的酶的差异表达，这些酶有助于确定个体易感性。分子方法已被积极应用于多项职业/环境致癌物暴露研究。虽然暴露生物标志物的估计在DNA损伤和加合物方面肯定显示出预期效果，但暴露生物效应的检测（例如在染色体改变水平）并非如此明确。与不吸烟者相比，将吸烟者作为一个群体进行检查时也是如此。几种标志物（尤其是染色体损伤和突变的标志物）与年龄有很强的相关性，这表明随着年龄增长对损伤的易感性增加，或者长期变化的积累。DNA修复——在损伤导致突变之前将其清除的关键因素——在个体之间可能存在差异，并且可能受到内在或外在因素的调节，但由于缺乏可靠的检测方法，可用数据有限。关于其他决定个体易感性的酶的信息确实存在，并且已经出现了一些表型或基因型多态性的显著影响，尽管各种酶之间的相互作用使情况非常复杂。正常细胞中氧化DNA损伤是否会因膳食抗氧化剂（水果和蔬菜中的维生素C、类胡萝卜素等）而减少这一重要问题已在抗氧化剂补充实验中得到解决。使用验证不佳的碱基氧化检测方法无助于我们得出明确答案；似乎无论如何，氧化损伤的程度都被大大夸大了。DNA损伤剂会导致特征性的碱基变化（转换、颠换、缺失）。对肿瘤组织中研究的癌症相关基因突变谱的调查应该能够更好地了解最终导致肿瘤的因子。同样，研究中性标记基因（不参与肿瘤发生）中的突变可以告诉我们“背景”突变水平的起源。到目前为止，对不断增长的数据库的解释很大程度上是推测性的。
