The molecular epidemiology of oxidative damage to DNA and cancer.
The molecular epidemiology of oxidative damage to DNA and cancer.
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DOI：
10.1093/jnci/djg065
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发表时间：
2003-09
期刊：
影响因子：
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通讯作者：
N. Caporaso
中科院分区：
文献类型：
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作者：
N. Caporaso
氧气是呼吸和维持有氧生活的能量过程所必需的。与氧气使用相关的成本是自由基的形成，这会破坏基因组的稳定性，并导致各种过程，包括衰老，退行性疾病和癌症（1，2）。包括水果、蔬菜、茶成分和反式脂肪在内的食物;包括维生素C和E、硒、β-胡萝卜素和膳食鱼油在内的营养素;化疗药物;辐射;感染;包括空气污染在内的环境暴露;以及遗传和后天条件广泛地促进或对抗自由基形成和基因组损伤（2-9）。单独和合作，氧化DNA损伤的调节剂的作用是激烈的研究和争议的焦点（10）。了解自由基形成的调节及其后果可能会为癌症的病因学提供新的见解，并导致有效的化学预防剂的发展。肺癌是评估氧化损伤和自由基作用的合理疾病，因为肺癌的病原体是已知会损伤DNA的烟草致癌物（11）。为了了解DNA修复活性在肺癌中的作用，需要在分子流行病学研究中开发并在人群中测试准确、可重复和特异性的表型测定。这些研究的结果表明，DNA修复活性降低的受试者（通过各种测定法测量）患肺癌的风险增加。存在多种评估氧化性DNA损伤的分析技术，最近已对其进行了综述（12）。在本期杂志中，Paz-Elizur等人（13）描述了氧化损伤8-氧代鸟嘌呤的DNA修复试验。作者发现，8-氧代鸟嘌呤DNA N-糖基化酶（OGG）活性在可手术肺癌受试者中降低。在这里，我评论的分子流行病学研究设计的背景下，这些研究结果的影响。分子流行病学研究的一般挑战和陷阱，包括关键的验证步骤，已被全面审查（14）。为了评价氧化修复表型，即，假定宿主具有稳定的修复特定类型的氧化DNA损伤的能力，已知这种损伤是由包括吸烟在内的致突变性损伤引起的，在分子流行病学研究中可以解决五类问题（图1）。第一类是氧化修复表型和任何广泛的流行病学暴露之间的关系。这是基本的，不仅因为理解测定与基本人类差异的关系（即，年龄和性别）有助于验证，而且还因为DNA修复测定和肺癌之间的推定关系必须与肺癌相关暴露对测定本身的影响区分开来。在肺癌中，重要的是要在一开始就确定氧化修复表型是否与吸烟有关，因为烟草烟雾中的许多化学物质包括致癌物质，这些物质可能会耗尽抗氧化剂或诱导其他改变，如氧化DNA碱基修饰（15）。如果检测结果受到烟雾的干扰-
Oxygen is required for respiration and the energetic processes that enable aerobic life. A cost associated with oxygen use is free-radical formation, which damages genome stability and contributes to various processes including aging, degenerative diseases, and cancer (1,2). Foods including fruits, vegetables, tea components, and trans-fats; nutrients including vitamins C and E, selenium, beta-carotene, and dietary fish oil; chemotherapeutic drugs; radiation; infection; environmental exposures including air pollution; and hereditary and acquired conditions broadly contribute to or oppose free-radical formation and genomic damage (2–9). Individually and cooperatively, the action of modulators of oxidative DNA damage is the focus of intense study and controversy (10). Understanding the regulation of free-radical formation and its consequences may provide new insight into the etiology of cancer and lead to the development of effective chemoprevention agents. Lung cancer is a logical disease for evaluating oxidative damage and the role of free radicals because the etiologic agents for lung cancer are tobacco carcinogens that are known to damage DNA (11). To understand the role of DNA repair activity in lung cancer, accurate, reproducible, and specific phenotype assays need to be developed and tested in human populations in molecular epidemiology studies. Results from such studies have shown that subjects with reduced DNA-repair activity, as measured by a variety of assays, have an increased risk of lung cancer. A variety of analytical techniques to assess oxidative DNA damage exist and have been recently reviewed (12). In this issue of the Journal, Paz-Elizur et al. (13) describe a DNA repair assay for the oxidative lesion 8-oxoguanine. The authors find that the 8-oxoguanine DNA N-glycosylase (OGG) activity is reduced in subjects with operable lung cancer. Here, I comment on the implications of these findings within the context of molecular epidemiology study designs. The general challenges and pitfalls of molecular epidemiology studies including critical validation steps have been comprehensively reviewed (14). For evaluating the oxidative repair phenotype, i.e., a presumably stable host ability to repair a specific type of oxidative DNA damage known to result from mutagenic insults including tobacco smoking, there are five general categories of questions that can be addressed in a molecular epidemiology study (Fig. 1). The first category is the relation between the oxidative repair phenotype and any of a broad range of epidemiologic exposures. This is fundamental not only because understanding the relation of the assay to basic human differences (i.e., age and sex) contributes to validation, but also because a putative relation between the DNA repair assay and lung cancer must be distinguishable from an effect of exposures associated with lung cancer on the assay itself. In lung cancer, it is important to establish at the outset whether the oxidative repair phenotype is associated with smoking, because the numerous chemicals in tobacco smoke include carcinogens that could deplete antioxidants or induce other alterations such as oxidative DNA base modifications (15). If the assay results are confounded by smok-