The molecular epidemiology of oxidative damage to DNA and cancer.

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-