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Charge to Participants and Workshop Objectives

REMARKS AND CHARGE TO PARTICIPANTS

Samuel H. Wilson

As I am sure you will all agree, we have accumulated a wealth of knowledge about cancer through many years of investment in fundamental and applied research. During this time, many promising drugs and treatments have been discovered, and survivorship and prevention are increasing. We have begun to unravel the mysteries of the molecular architecture of cancer, and this has revealed that cancer is not a singular disease. It is, rather, a closely linked group of molecular disorders, varying in etiology and mechanism, but with some common intersections. Additionally, we know that a person’s susceptibility to cancer can be governed by the interaction of common modifier genes or “susceptibility genes” and environmental factors.

It is clear that if we are to continue making progress in prevention and treatment of cancer, we will have to place additional focus on the interplay between modifier genes and environment. It is this interplay that holds the greatest promise in the fight to prevent and control cancer—a central theme of this workshop.

Workshops such as this assist members of the Institute of Medicine Roundtable on Environmental Health Sciences, Research, and Medicine in clarifying issues concerning environmental health. The presentations and discussions further define the topics that will be important for the Roundtable to discuss and consider in the future. When the Roundtable met in September of 2000, it became evident that this was an ideal time to hold a workshop on gene–environment interactions in cancer because of two recent advances in genetics and environmental studies. The first advance is the completion of an initial draft sequence of the human genome. We now are in the early stages of the postsequencing genomics era, and we are beginning to comprehend the genetic variations that



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Cancer and the Environment: Gene-Enviroment Interaction 1 Charge to Participants and Workshop Objectives REMARKS AND CHARGE TO PARTICIPANTS Samuel H. Wilson As I am sure you will all agree, we have accumulated a wealth of knowledge about cancer through many years of investment in fundamental and applied research. During this time, many promising drugs and treatments have been discovered, and survivorship and prevention are increasing. We have begun to unravel the mysteries of the molecular architecture of cancer, and this has revealed that cancer is not a singular disease. It is, rather, a closely linked group of molecular disorders, varying in etiology and mechanism, but with some common intersections. Additionally, we know that a person’s susceptibility to cancer can be governed by the interaction of common modifier genes or “susceptibility genes” and environmental factors. It is clear that if we are to continue making progress in prevention and treatment of cancer, we will have to place additional focus on the interplay between modifier genes and environment. It is this interplay that holds the greatest promise in the fight to prevent and control cancer—a central theme of this workshop. Workshops such as this assist members of the Institute of Medicine Roundtable on Environmental Health Sciences, Research, and Medicine in clarifying issues concerning environmental health. The presentations and discussions further define the topics that will be important for the Roundtable to discuss and consider in the future. When the Roundtable met in September of 2000, it became evident that this was an ideal time to hold a workshop on gene–environment interactions in cancer because of two recent advances in genetics and environmental studies. The first advance is the completion of an initial draft sequence of the human genome. We now are in the early stages of the postsequencing genomics era, and we are beginning to comprehend the genetic variations that

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Cancer and the Environment: Gene-Enviroment Interaction modify an individual’s susceptibility to cancer. The second development is that we are working with an evolving, expanded, and enhanced view of environmental health and exposures that includes factors such as diet, lifestyle, metabolic alterations, socioeconomic status, and environmental pollutants. It is this expanded view of environmental health that will allow us to conduct more meaningful and precise studies of environmental contributions to cancer. Although the research model of the rare dominant cancer gene, or the strong environmental toxicant, has served us well in the past in defining the molecular biology of cancer, it will not be sufficient in the future. Only a small percentage of cancer is attributable to powerful dominant single genes or the strongest toxicants. Instead, new science and a new scientific toolbox will be needed, and more research involving the common modifier genes and the multiple environmental factors must be considered. Fortunately, the genomics era can provide us with many of these new tools. Cancer research in the future will require an integration of new molecular genetic measurements, environmental exposure measurements, and precisely defined population groups. As the group planning this workshop explored the themes and questions surrounding gene–environment interactions, we identified a number of key unanswered questions. I list these as a challenge and a charge to our speakers, panelists, and participants to consider during the workshop: What are the approaches and the assay tools that will allow us to conduct the most precise molecular evaluations of cancer susceptibility? What are the approaches that will allow us to understand the lag time or the interval between the earliest stages of precancer and the eventual clinical end points of cancer? What are the research strategies that will allow us to measure the multiple stages during cancer development so that early interventions can be facilitated? How will we apply information on genetic and environmental factors to reduce the burden of cancer through education, prevention, and intervention? How can this be done in ways that are both sensitive to local community needs and flexible enough to allow individual approaches? All of these questions are difficult and open ended. Even though we may not find all of the answers, this workshop will help us to frame approaches in the future and to find the answers more rapidly. We must rise to the challenge of understanding the complex equation of gene–environment interaction and apply this understanding to the prevention and treatment of cancer. This is a time of great promise for environmental cancer research as we are poised to use new technologies and multidisciplinary approaches to further unravel this devastating disease we call cancer.

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Cancer and the Environment: Gene-Enviroment Interaction STATEMENT OF WORKSHOP OBJECTIVES Franklin Mirer Cancer is still the second leading cause of death in the United States; more than half a million lives are claimed each year. For industrial workers, occupation-related cancer is responsible for 5 to 20 times the number of work-related deaths as traumatic injury. After decades of steady increases in cancer death rates, the 1990s saw the beginning of a downward trend. Fortunately, cancer survival rates have increased, in large part because of earlier detection, screening programs, and advances in chemotherapy and other treatments. These positive trends, however, are only part of the story, because the incidence of certain cancers is still on the rise. Both environmental and genetic factors are involved in the development of cancer. In fact, one of the earliest observations of an environmental cause of cancer was reported by Bernardino Ramazzini in 1714. Today, we know that exposure to chemicals and sunlight, diet, lifestyle, economic status, and infections can contribute to the development of certain cancers. Yet not everyone exposed to a particular cancer-causing agent or chemical develops the disease. For example, 90 percent of heavy smokers do not get cancer. Complex interactions require future research on individual susceptibilities, examining how multiple modifier genes interact with the environment. Since the 1960s we have been developing the field of occupational health along a particular paradigm that has three main questions. First, does a carcinogenic effect at a higher exposure exist at lower exposures? Second, does a carcinogenic effect observed in a laboratory animal study reliably predict a carcinogenic effect in people? Third, are there enough people exposed to identified carcinogens at high enough levels to account for a significant fraction of observed cancers? It is important to study the interactions of all the factors that influence health. For example, if an investigator does not know anything about chemical exposures, then he or she might conclude that all of the variations of cancer rates in the populations are based on genetics or other host factors. Actually, if everyone in a particular population has the same exposure, all the variation will be due to host factors. Second, if an investigator does not know anything about genetics, he or she will presume that all variation in cancer rates is due to exposure. Finally, if an investigator focuses on only one carcinogen, then he or she will overattribute the role of that agent in all cancers. Over the past 40 years, we have reached a limited consensus on what environmental agents contribute to the development of cancer. As we use new information to evaluate the carcinogenic risks of chemicals, we must also look backward at how hard it was to draw the final conclusions about the largest single cause of preventable mortality—cigarette smoking.

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Cancer and the Environment: Gene-Enviroment Interaction As noted earlier, this workshop is being held at a time when new technologies and new intellectual perspectives are available to push research into new research frontiers. This workshop was designed to bring together clinicians, epidemiologists, researchers, technologists, public health practioners, policymakers, and other interested parties to discuss the recent opportunities in cancer research. We will discuss many of the opportunities for areas of future research and prevention. Finally, we will use the broader perspective of environments—one that encompasses the effects of the social, built (including occupational), and natural environment—to begin to understand why not everyone or every group that is exposed to an environmental stressor develops cancer.