Basic biological research in tobacco-related carcinogenesis focuses on identifying genetic and epigenitic events that contribute to cancer and what can be done to prevent these cancers from occurring. INTRODUCTION We now know that a series of changes in gene function and activities that control cell growth and behavior transform normal cells into cancer. The components of tobacco smoke clearly cause genetic and other changes that lead to cancer. Because of this, tobacco use causes more than 30 percent of all cancer deaths and as much as 90 percent of all lung cancers. Basic biological research, which is enhanced by sophisticated new genetic and biochemical research techniques, is changing our understanding of carcinogenesis. It is critical that basic scientists formulate new hypotheses about carcinogenesis that include the role of tobacco and the route of exposure (active smoking, passive exposure, smokeless tobacco products). Moreover, experiments using the latest research tools, such as genetically engineered animal and cell lines, must include tobacco carcinogens. Understanding the complex characteristics of tobacco products is necessary if we are to learn how tobacco causes cancer. The burning of tobacco products leads to the production of over 3,800 chemicals, including known human mutagens and carcinogens. Although cancer-causing chemicals have been found in tobacco-smoke vapor, the majority of chemicals that lead to mutations and cancer reside in tobacco smoke particulates. Limited information is available about the molecular mechanisms of damage caused by tobacco smoke within specific organs. Even less is known about why tobacco smoke components target particular genes. Research to determine whether harmful tissue changes in one organ predict similar changes in others could lead to new ways to detect, diagnose, and treat cancer in its earliest stages for individual patients. In addition, basic biological research can lead to important insights about why some people may be especially vulnerable to harm from tobacco. For example, research may explain why women might be more susceptible to tobacco-related cancers than men, and why lung cancer risk for former smokers remains higher than for individuals who have never smoked (although much less than current smokers). RECOMMENDATIONS Basic biological research should be conducted to identify and validate biomarkers of tobacco exposure and tobacco-induced cellular events as they relate to the different stages of carcinogenesis. Expanding research is essential to identify, validate, and increase the availability of biological markers. Such research can provide the tools to determine the amount and type of carcinogens in individuals exposed to tobacco products. Examples of biological markers include carcinogen-macromolecular adducts, assays to measure enzymes involved in critical cellular processes, methods to detect DNA damage and decreased DNA repair, RNA-based methods to identify changes in expression, genetic variations that increase vulnerability or resistance to cancer-causing chemicals, and metabolites of procarcinogens or cancer-causing agents. The development of new biomarkers is dependent on the basic biological research of tobacco carcinogenesis. An understanding of the effects within, and by, cancer susceptibility genes will lead to the identification of genes that should be targeted for biomarker development. Similarly, research into the stages of carcinogenesis will be important for identifying biomarkers that can mark cancer progression. Basic biological research on tobacco smoke should focus on specific tumor-enhancing or prevention strategies, such as the role of dietary (e.g., antioxidants), environmental (e.g., radon, air pollution) and occupational (e.g., asbestos, metals) factors. Smoked, and smokeless tobacco, filtered and unfiltered cigarettes, and high- and low-nicotine tobacco all result in exposure to different types and amounts of carcinogens. Yet, little research has been done to specify and determine the amount of these carcinogens and to assess the changes in the profile of the carcinogens over time. Further, the effects of the burning temperatures (pyrolysis) on the most commonly used tobacco additives have not been investigated to any degree. Other areas that have not been studied adequately are how tobacco smoke components interact with each other and what synergies might exist. The development of biomarkers that can measure these effects and differences can provide a critical understanding of why we see variations in cancer incidence, what has caused changes in lung cancer histology over the last 40 years, and why there may be differences in risk between gender or races. THE IMPACT OF BASIC BIOLOGICAL RESEARCH The development of biomarkers for cancer risk can lead to the development of early detection methods and perhaps provide information about tumor responses to treatment. If development and validation of biological markers will allow testing, then we can test different prevention strategies by assessing changes in specific markers. In summary, if we gain a better understanding of human metabolic pathways through which the chemicals in tobacco cause their cancer-causing changes and identify the critical steps in those pathways that lead to increased susceptibility to tobacco-related cancer, then we will be better able to identify individuals at greatest risk for tobacco-related diseases and devise prevention strategies for them.