Summary

Cancer is the second leading cause of death in the United States and results in more than half a million deaths each year. In the 1990s, we began to see a downward trend in cancer death rates with an increased survival rate of cancer patients. Most of the increase in survival rates can be attributed to earlier detection through screening programs and advances in chemotherapy. However, what these positive trends mask is the fact that the incidence of some cancers is still on the rise.

Both environmental and genetic factors are known to be involved in the development of cancer. For example, environmental factors such as exposures to certain chemicals or to sunlight have long been linked to the development of some types of cancers. In planning this workshop, the Roundtable on Environmental Health Sciences, Research, and Medicine wanted to address the link between environmental factors and the development of cancer in the light of recent advances in genomics and, more specifically, in toxicogenomics and gene–environment interactions. Speakers were invited from many scientific discliplines including epidemiology, molecular biology, oncology, microbiology and immunology, nutrition science, and human genetics. The goals of the workshop were to facilitate discussion among these scientists; to assess genetic–environmental interactions across diverse populations, including the underserved, women, children, and minorities; and to review what is known about gene–environment interactions in site-specific cancers. The language presented in this summary should not be viewed as an endorsement by the Roundtable on Environmental Health Sciences, Research, and Medicine or the Institute of Medicine of what action is needed for the future, but rather as an effort to synthesize the various perspectives presented.

This workshop came at a logical time to begin asking complex questions about gene–environment interactions. As discussed by Samuel Wilson, National Institute of Environmental Health Sciences, only a small percentage of cancer is attributed to the powerful dominant single genes or the strongest toxicants. With



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Cancer and the Environment: Gene-Enviroment Interaction Summary Cancer is the second leading cause of death in the United States and results in more than half a million deaths each year. In the 1990s, we began to see a downward trend in cancer death rates with an increased survival rate of cancer patients. Most of the increase in survival rates can be attributed to earlier detection through screening programs and advances in chemotherapy. However, what these positive trends mask is the fact that the incidence of some cancers is still on the rise. Both environmental and genetic factors are known to be involved in the development of cancer. For example, environmental factors such as exposures to certain chemicals or to sunlight have long been linked to the development of some types of cancers. In planning this workshop, the Roundtable on Environmental Health Sciences, Research, and Medicine wanted to address the link between environmental factors and the development of cancer in the light of recent advances in genomics and, more specifically, in toxicogenomics and gene–environment interactions. Speakers were invited from many scientific discliplines including epidemiology, molecular biology, oncology, microbiology and immunology, nutrition science, and human genetics. The goals of the workshop were to facilitate discussion among these scientists; to assess genetic–environmental interactions across diverse populations, including the underserved, women, children, and minorities; and to review what is known about gene–environment interactions in site-specific cancers. The language presented in this summary should not be viewed as an endorsement by the Roundtable on Environmental Health Sciences, Research, and Medicine or the Institute of Medicine of what action is needed for the future, but rather as an effort to synthesize the various perspectives presented. This workshop came at a logical time to begin asking complex questions about gene–environment interactions. As discussed by Samuel Wilson, National Institute of Environmental Health Sciences, only a small percentage of cancer is attributed to the powerful dominant single genes or the strongest toxicants. With

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Cancer and the Environment: Gene-Enviroment Interaction the recent completion of an initial draft sequence of the human genome and with the evolving and enhanced view of environmentmental health, we will be able to conduct more precise studies of environmental contributions to cancer. He further suggested that we will need a new toolbox to address cancer resulting from the common modifier genes and multiple environmental exposures. In the charge to the speakers and participants, he outlined a number of questions that would begin to address what research tools will be needed, how new scientific information can be applied in a timely manner to reduce the burden of cancer, and how this can be flexible enough to treat the individual. Sam Donaldson, of ABC News, opened the meeting with a keynote address in which he described the media’s tendency to seek out scientific outliers rather than the conventional wisdom. He urged the scientific community to be clear in its messages about the linkages between cancer and the environment and to emphasize areas of agreement. THE ROLE OF THE ENVIRONMENT IN CANCER In a scientific keynote address, Joseph Fraumeni, National Cancer Institute, highlighted the importance of environmental factors in human cancer. He pointed to a growing body of knowledge that dramatically illustrates the influence of such factors, for example, the observations of scrotal cancer among young chimney sweeps in London in 1775 and the international variation reported in cancer incidence. John Milner, Pennsylvania State University, using a broader perspective of environment—one that includes diet and lifestyle, described the evidence of dietary interactions and cancer. He discussed the findings that both essential and nonessential dietary nutrients can markedly influence several key biological events, including cell cycle regulation, processes involved in replication or transcription, immunocompetence, and factors involved in apoptosis, or programmed cell death. These observations suggest that specific foods or components may have the potential to markedly reduce cancer risk. Analyses of the incidence of cancer in twin pairs and in families are traditional methods for answering questions about the relationships between cancer etiology, genes, and the environment. Kari Hemminki, Karolinska Institute, and Curtis Harris, National Cancer Institute, described recent progress in identifying and characterizing susceptibility genes in familial cancer. This work, taken together, has revolutionized our understanding of the critical genetic mechanisms in cancer etiology. Studies that combine genetic analysis with assessment of exposures and diet can explain why not everyone exposed to a particular cancer-causing chemical will develop cancer. Recent research has identified functional polymorphisms that influence an individual’s cancer risk and has focused on gene products involved in the activation and detoxification of carcinogens and DNA repair. Gene polymorphisms that are important in apoptosis will increasingly be recognized as clues to individual susceptibility to cancer.

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Cancer and the Environment: Gene-Enviroment Interaction SPECIAL POPULATIONS Despite recent good news about decreasing cancer mortality rates, not all population subgroups are sharing in this success story. Cancer rates are higher and accelerating in some racial and ethnic groups. The reasons for these disparities may include the environment, hormones, and genetics. Lovell Jones, M.D. Anderson Cancer Center, described how progress toward preventing, diagnosing, and treating cancer will be hampered by the nation’s inability to deal effectively with the greater cancer burden borne by certain vulnerable populations. These populations are typically defined as groups at higher-than-average risk of death, disease, and disability, and include people with low incomes, low literacy rates, the elderly, those in rural communities, African Americans, Hispanics, American Indians and Alaska Natives, and other ethnic minorities. Trying to assess how genes and the environment compound cancer risk in populations considered vulnerable because of their social or economic status requires new approaches, according to some workshop participants. Demographic studies of cancer must consider the diversity within affluent groups as well as within less economically affluent groups, said Armin Weinberg, Baylor College of Medicine. They also must consider immigration patterns and countries of origin because those factors play a primary role in predisposition to cancer. María Hernández-Valero described how populations, such as migrant farmworkers and children, are particularly vulnerable to developing cancer following environmental exposures. Farmworkers, who include pregnant women and chil- A number of questions concerning future research emerged from the workshop: If we move toward large-scale clinical trial studies and large-scale population studies, how (and by whom) will the large repositories for DNA and tissues be created? If large amounts of lifestyle, medical, and environmental exposure information are needed, do we have the resources necessary to collect and organize this information? How will we solve policy issues related to access to databases, while maintaining protection of patient rights? How do we encourage more “discovery-driven” research to define the molecular landscape of cancer? How can this be incorporated into an interdisciplinary research involving epidemiologists and molecular biologists? With the greater emphasis on environmental surveillance and environmental disease registries, how do we ensure that all populations, including special populations, are involved?

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Cancer and the Environment: Gene-Enviroment Interaction dren, endure a high burden of exposure to pesticides and other agents that are known carcinogens. The extent of the burden is unknown because it is particularly difficult to study exposures and cancer clusters in migrant farmworkers due to their mobility and hesitancy to be the subjects of investigation, said Richard Jackson, Centers for Disease Control and Prevention. Starting in infancy, children are vulnerable to environmental exposures. Greta Bunin, Children’s Hospital of Philadelphia, and Leslie Robison, University of Minnesota, discussed trends in incidence and survivorship in childhood cancers and presented preliminary evidence about linkages between childhood cancer and diet. In addition to in utero exposures and, in some cases, preconceptual exposures of the parents, diet and other environmental influences may combine with genetic predispositions to form a strong link between these factors and the development of childhood cancers. The developing child may be particularly sensitive to exposures affecting specific organs, since the types of cancer found in children are disproportionately different from those found in adults. Some meeting participants suggested that longitudinal studies are needed to be able to identify risk factors. SITE-SPECIFIC CANCERS Presenters described some recent advances in understanding the linkages between genes and the environment in site-specific cancers, including breast, lung, colorectal, and prostate cancer. More refined studies have been focused on understanding how genetics may account for the differences among individuals in their responses to harmful exposures. For example, John Minna, University of Texas Southwestern Medical Center, and Margaret Spitz, M.D. Anderson Cancer Center, described how some genes signal the synthesis of enzymes in the lung. Ordinarily these enzymes destroy cancer-causing substances in tobacco smoke, but a gene variation might reduce these enzymes or their efficiency, and therefore make people more susceptible to lung cancer. Understanding the role of environment in breast cancer is an area of ongoing research. Brian Henderson, University of Southern California; Mary Wolff, Mount Sinai School of Medicine; and Olufunmilayo Olopade, University of Chicago, discussed studies under way to address how complex genetic factors or hormonal milieu may alter environmental risk factors. These effects may be responsible for differences in breast cancer among racial or ethnic groups. Presentations by Raymond DuBois, Vanderbilt University, and David Alberts, Arizona Cancer Center, highlighted what is known about environmental risk factors in the development of colorectal cancer. Understanding the twentyfold variation in incidence rates in different geographic regions around the country may provide a clue to the etiology of colorectal cancer. In addition, studying the relationship of the environment and adenomatous polyps—the precursors to colorectal cancer—may help identify relatively asymptomatic individuals who

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Cancer and the Environment: Gene-Enviroment Interaction are at increased risk of cancer and would benefit most from diagnostic follow-up or intervention. Development of multigenic models of cancer susceptibility will be an important future approach to predicting, preventing, and diagnosing cancers, said some participants. For example, prostate cancer is a common disease for which there are few well established risk factors. Pedigree analyses suggest a genetic component for some individuals; however, the majority of prostate cancer cases cannot be explained by a single-gene model, suggesting multigenic etiology. Moreover, the international and racial–ethnic variations in prostate cancer incidence, combined with the effects of migration on risk patterns, suggest that gene–environment interaction may be involved in determining prostate cancer risk. Donald Coffey, Johns Hopkins University, and Robert DiPaola, Cancer Institute of New Jersey, discussed the relative roles of diet, nutritional supplements, and hormones in risks for prostate cancer. Finally, one area of research has focused on using the body’s own immune response to combat the growth and development of cancer. Steven Rosenberg, National Cancer Institute, described how these so-called immunotherapies are in their initial stages but offer much hope for future vaccines and treatment approaches. Several speakers emphasized the need for combining cancer registry data with other databases to identify new etiologic leads. For example, large epidemiologic consortia could be formed to pool data and publish results from several independent investigations to quickly determine whether a given result in one study is supported by other studies. Some participants also noted the need for a linked environmental surveillance system. Investigations of the cancer-related significance of hormonal, metabolic, genetic, and environmental factors could then be compared and contrasted. Additionally, some workshop participants suggested that we need better technologies and generally enhanced skills in the area of risk communication. The combination of these efforts could lead to better cancer prevention and control.

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