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Cancer and the Environment: Gene-Enviroment Interaction 4 Gene–Environment Interaction in Special Populations One of the challenges in cancer research and prevention is to ensure that the benefits in cancer prevention and treatment are available to individuals from all areas of the United States regardless of gender, socioeconomic status, age, ethnic origin, or migration. The workshop planning group, recognizing the need to look at research in diverse communities, devoted a session of the agenda to discuss advances and research in these areas. One challenge according to Armin Weinberg, Baylor College of Medicine, is the need to continue to describe and understand what researchers call special populations, priority populations, and vulnerable populations. “It is important to describe these populations, but not to label them” said Weinberg. As we continue to go forward in our research, we will most likely find that within communities and groups, there are subgroups. These subgroups will have issues and special circumstances that will have to be addressed. HEALTH DISPARITIES According to Lovell Jones, M.D. Anderson Cancer Center, “When we approach efforts to deal with the lack of real progress in addressing health disparities, we tend to fall back on what we did before. It may be under a different name or it may be packaged in a different box, but ultimately it is the same strategy. In other words, if you always do what you have always done, we will always get what we already got.” He added that more data are needed to document the reality of health disparities, to characterize them accurately, and to determine their causes. Disparities are not necessarily racially or ethnically linked; they can be associated with lack of insurance, access to medical care, age, employment status, and migration patterns. Nonethe- We need new approaches to effectively deal with health disparities. Lovell Jones
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Cancer and the Environment: Gene-Enviroment Interaction less, minorities, the poor, the medically underserved, and children suffer disproportionately from these burdens in terms of health disparities. In some racial and ethnic groups, cancer rates are higher and accelerating, according to Jones (see Newell, 1988). The reasons for these disparities may include the environment, hormones, and genetics but also involve socioeconomic status. “Although racial classifications are a social construct, these classifications continue to have an impact on the health of this nation,” said Jones, adding that “health is probably the best indicator of the failure of this nation to address the issue of skin color and social class and the future well-being of this nation.” Because we do not apply what we know about prevention and treatment equally to all parts of society, we are not achieving the health gains that are currently possible. Because we do not apply what we know about prevention and treatment equally to all parts of society, we are not achieving the health gains that are currently possible. Lovell Jones Higher income permits increased access to medical care and enables people to afford better housing, live in better neighborhoods, and have opportunities to promote their health behaviors. Higher incomes also tend to help people participate in clinical research studies, said Weinberg; thus, disparities in access to health care can affect enrollment in research studies. Demographic studies of cancer must consider the diversity within affluent groups as well as within less economically affluent groups. INFLUENCE OF MIGRATION Researchers have to consider immigration patterns and countries of origin because these factors play a primary role in predisposition to cancer. Individuals from many geographic locations have different diets, exposures, and degrees of acculturations but are commonly grouped together. For example, the “Hispanic” group in the United States consists of individuals who have migrated from Mexico, South America, Cuba, the U.S. territory of Puerto Rico, as well as those born in the United States. Further, even though the vast majority (64–65 percent) of all Hispanics in the United States are Mexican Americans, there may be differences among this group. As seen in Figure 4-1, three distinct Mexican American populations have migrated to the United States. Although they are all grouped as Mexican Americans, they will have some differences in diet and exposure. What this suggests is that the outcomes of a study of Hispanics in Texas may differ from those of Hispanics in California. As we address issues in cancer, “we need to remember that one size does not fit all,” said Jones. Within special populations, vulnerable groups, or ethnic minorities, we have to remember that not all members are the same polymorphically and that children are not small adults.
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Cancer and the Environment: Gene-Enviroment Interaction FIGURE 4-1 Geographical influence on migration. Migration patterns from Mexico show three distinct Mexican American populations that have migrated to the United States. SOURCE: L. Jones unpublished. Reprinted with permission. CANCER DISPARITIES IN APPALACHIA The National Cancer Institute (NCI) has stated that it considers rural residents to constitute a vulnerable population because rural Americans tend to be older, poorer, less educated, and more likely to be uninsured than their urban counterparts. In addition, rural communities have higher rates of chronic illness and disability and report poorer overall health status than urban communities. Residents in rural areas generally have less contact and fewer visits with physicians and lower levels of preventive care. In addition to factors related to rural health status and practices, there are systemic factors related to rural life in general—for example, lack of public transportation and lower levels of other community services—that may also contribute to less-than-optimal cancer control. All of these factors are evident in the largely rural and predominantly white population of Appalachia, particularly in the Central Highlands, said Gilbert Friedell of the Markey Cancer Control Program in Lexington, Kentucky. Age-
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Cancer and the Environment: Gene-Enviroment Interaction TABLE 4-1 Age-Adjusted Cancer Incidence Rates (per 100,000 population), 1995–1997 Kentucky Site Overall White Black Appalachiaa Lung 85.03 84.35 97.18 98.25 Invasive cervix 10.99 10.82 13.76 13.34 aBig Sandy, Kentucky River, and Cumberland Area Development Districts. SOURCE: Friedell et al. (1999). Reprinted with permission (Kentucky Cancer Registry). adjusted cancer mortality rates for Appalachia are higher than those in the rest of the United States. Lung cancer is a leading cause of male cancer deaths in central Appalachia—with the highest incidence in Appalachian Kentucky, the geographic area with the highest rate of cigarette smoking in the state. The incidence of invasive cervical cancer and lung cancer in eastern Kentucky is higher than the incidence of these cancers in the overall Kentucky population (see Table 4-1). It is, however, quite similar to the incidence of lung cancer and cervical cancer in the predominantly urban, African American population of Kentucky. Poverty is a common characteristic of these two groups, said Friedell. Some of the counties in Appalachian Kentucky, for example, are among the poorest in the country and have the lowest levels of literacy. The use of race and ethnicity as surrogates for poverty has obscured the fact that the problems related to cancer in the poor white population are comparable in many ways to those seen in recognizable minority populations, added Friedell. The use of race and ethnicity as surrogates for poverty has obscured the fact that the problems related to cancer in the poor white population are comparable in many ways to those seen in recognizable minority populations. Gilbert Friedell Individuals living in poverty often do not receive quality health care, including cancer prevention, diagnosis, treatment, and appropriate follow-up care because services are not available, accessible, or utilized. In addition, certain behavioral risk factors, such as tobacco use, poor nutrition, obesity, and underutilization of cancer screening examinations, are more prevalent in impoverished populations. Friedell pointed out that “the social environment in which poor people live prevents the development of healthy behaviors.” However, until cancer surveillance incorporates socioeconomic status, the relationship between poverty and cancer in population groups will be difficult to sort out, said Friedell.
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Cancer and the Environment: Gene-Enviroment Interaction Some barriers to increased participation in cancer control programs exist at all socioeconomic levels, for example, lack of information about cancer and about the availability and the benefit of cancer screening. Other barriers, such as feelings of isolation and low literacy, are more prevalent in low-income, medically underserved populations such as those in Appalachia, said Friedell. For example, the average Kentucky high school completion rate was 65 percent, while the rate in Appalachian Kentucky counties was 55 percent. This barrier needs to be recognized by physicians and other health care personnel. The NCI, recognizing the cancer control problems in Appalachia, has funded the Appalachia Leadership Initiative on Cancer for seven years as well as individual research projects in the region. Much of this effort has been aimed at the community level. Lessons drawn from this program indicate that enhancing cancer control efforts at the community level is possible, but it is labor intensive and requires commitment at the state and national levels and recognition that ongoing support will be necessary, concluded Friedell. MIGRANT FARMWORKERS’ CHILDREN AND PESTICIDES: A HIGH-RISK POPULATION There are approximately 3 million to 6 million migrant and/or seasonal farmworkers (MSFs) in the United States. Approximately 85 to 90 percent are from ethnic and racial minorities, including Hispanics, African Americans, and Caribbean islanders. However, Hispanics of Mexican descent constitute the majority of this population, with children and adolescents comprising 20 to 25 percent of the total population. MSF children are chronically exposed to pesticides because of their parents’ occupation. This exposure is of great concern given the vulnerability of children as determined by their body size and continuous development, which can increase the carcinogenic effects of these chemicals, according to María A. Hernández-Valero, M.D. Anderson Cancer Center. There are several pathways by which these children can be exposed to agrochemicals at a very early age, including application drift; overspray; carry-home exposures from parents; exposure in utero; breast-feeding; going or working in the fields with their parents; and the foods they eat. Being chronically exposed to pesticides, some of which are known endocrine disrupters, may place MSF children who may also be genetically susceptible to these chemical substances at a higher risk of developing ill-health effects, including cancer. Studies of nonmigrant and agricultural workers also suggest that exposure to pesticides is associated with an increased risk of fetal death, miscarriages, developmental defects, and central nervous system disorders. Yet cancer research among these workers and their families is almost nonexistent, which is attributed to the perceived difficulty in conducting epidemiologic studies among this underrepresented population. Because organochlorine pesticides remain in the environment for many years
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Cancer and the Environment: Gene-Enviroment Interaction and MSF children are constantly exposed through many pathways, there is the need to monitor this high-risk population, said Hernández-Valero, and to consider options for reducing its pesticide exposures. Hernández-Valero recommends that these children be included in prospective cohort studies that are going on nationwide and that their exposure to pesticides be monitored to determine if chronic exposure at an early age will place them at a higher risk of developing deleterious health outcomes, including cancer, during childhood and later in life. CHEMICALS AND CANCER CLUSTERS “Cancer clusters are the bane of the existence of state and local health officials,” said Richard Jackson, Centers for Disease Control and Prevention, “yet there are real opportunities embedded in cancer clusters to meet public health needs, and they can actually end up with good outcomes if you use good communication skills, good science, good medicine, and bring good policy to all of this.” In the public’s mind, clusters are environmental until proven otherwise. Richard Jackson Jackson described his experience with pesticide use in Kern County, California, where agricultural chemicals have caused broad environmental contamination of wells with dibromochloro-propane, a known carcinogen that also causes sterility in males. Fifteen years ago, said Jackson, there was no way to deal with the public’s concerns about these chemicals. There were no cancer or birth defects registries in the Central Valley of California. In addition, there was no obligatory reporting of pesticide use unless it was Category One (extremely toxic), and there was no record-keeping on these chemicals. Thus, it was very difficult to do investigations in this area. When the data gaps on these chemicals were filled, it turned out that an important percentage of them contained reproductive toxins and teratogens, as well as chemicals that cause skin toxicity. Many of these “grandfathered” chemicals were not tested before being put in the field, and as a result, unusual illnesses occurred. Some children with birth defects that resembled those caused by thalidomide were born to women who had been exposed in the fields. Migrant workers are particularly vulnerable, said Jackson, because in many cases they are undocumented workers, are poorly educated, and do not speak English. They are loathe to complain and unwilling to cooperate with investigations for fear of deportation. This highlights the need for public health investigators to learn how to communicate with communities and anticipate their concerns. “Thinking that you can deal with clusters and community problems without an on-site community person is a mistake,” said Jackson. “Disease clusters are socially inexorable. You have to pay attention to them. You have to respond to people’s concerns. Clusters are extremely power-
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Cancer and the Environment: Gene-Enviroment Interaction ful socially and they are extremely powerful politically.” In the public’s mind, added Jackson, clusters are environmental until proven otherwise. As a result of an aggressive public health response and effective health advisory committees, there are now cancer and birth defects registries in the Central Valley of California. In addition, there is full record-keeping of all pesticide use in California in all toxicity categories. The challenge, said Jackson, is to actually document people’s precise level of exposures so as to more accurately calibrate risks. This has to be considered in view of genetic variations in response to exposures. Dealing with cancer clusters with open dialogue and aggressive diligence can convert them from dreaded inevitabilities into genuine public health opportunities. CANCER IN CHILDREN Observations during the past several decades have identified a modest but consistent increase in the incidence of childhood cancers. Secular trends have varied with specific diagnostic categories, but the most consistent increases have been seen in acute leukemia and in tumors of the central nervous system, said Leslie Robison, University of Minnesota. An ecologic association has been noted between increases in brain and central nervous system (CNS) tumors and increased utilization of imaging techniques, suggesting that earlier detection may account for some of the observed increases. Childhood cancer represents a relatively rare disease entity. In the general population, cancers in children under the age of 15 years are less than 2 percent of all the cancer burden in the United States. This is a small but important proportion, not only from what it can tell us scientifically but, more importantly, in terms of the number of years of potential life that are at stake, said Robison. In the United States, approximately 8,000 individuals under age 15 are diagnosed with cancer each year. The cumulative probability of a child developing cancer is approximately 1 in 630 before the age of 15 and 1 in 300 before the age of 20. Distinct age-specific patterns of incidence occur among specific diagnostic classifications within the pediatric and adolescent age groups. There is a peak in incidence of acute lymphoblastic leukemia between the ages of 3 and 6 years; neuroblastoma, retinoblastoma, and Wilms’ tumor aggregate in children less than 5 years old; lymphoma incidence rises with increasing age. Overall, males have a higher rate of malignancies than females, which is attributable primarily to a higher incidence of lymphomas and acute lymphoblastic leukemia among males. In the 15–20-year age group, females have a higher incidence of cancer than males. It is estimated that approximately 1 in every 900 individuals between the ages of 15 and 45 is now a survivor of childhood or adolescent cancer. Leslie Robison
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Cancer and the Environment: Gene-Enviroment Interaction The survival rate for childhood and adolescent cancer has increased dramatically during the past three decades. Currently, more than 70 percent of individuals diagnosed with cancer before age 15 will survive five or more years from diagnosis, with the majority being cured of their original malignancy. With these improvements in treatment and survival, it is estimated that approximately 1 in every 900 individuals between the ages of 15 and 45 is now a survivor of childhood or adolescent cancer. These survivors are, however, at increased risk for long-term complications of their initial cancer and subsequent therapy. Late sequelae of childhood cancer can include an increased risk of second and subsequent malignancies, as well as serious organ dysfunction and psychosocial effects. As more patients survive and the length of follow-up grows, patterns of second and subsequent malignancies are being identified in survivors, including increased rates of breast cancer, thyroid malignancies, CNS tumors, and leukemia. Robison is interested in research on the long-term outcomes of these cancer survivors. Typically, studies of long-term outcomes and risk of second malignancies focus on the modalities used in the successful treatment of a patient. “Most patients receive multi-modality treatments, and we need to look at the interaction of these treatments as well as genetic effects,” said Robison. The potential interaction between these treatments and the underlying genetics is of key importance and a high priority for study. Robison and others are piloting the creation of a national registry of children with cancer to identify environmental and other causes of cancer. CHILDHOOD CANCER AND DIET Diet can be considered part of the environment from several perspectives. All foods—including fish, fowl, meat, grains, vegetables, and fruits—may contain traces of contaminants such as pesticides used in food production and pollutants such as heavy metals and polychlorinated biphenyls. In addition, the nutrient composition of foods can vary with how and where the food is produced. Additives may be part of processing food. Fewer than 20 studies have focused on diet in relation to childhood cancer, perhaps because scientists have thought it unlikely to play a role. Adult cancers that are most strongly linked with diet rarely occur in children and have latency periods of several decades. Limited research on this topic, however, suggests that diet may indeed affect risk, at least of some childhood cancers, said Greta Bunin, Children’s Hospital of Philadelphia. The childhood cancer studied the most in relation to diet is brain cancer, said Bunin. According to one hypothesis, children with greater exposure to N-nitroso compounds (NOCs) and their precursors are more likely to develop a brain tumor compared to other children. In many species of animals, NOCs are highly potent carcinogens, inducing nervous system tumors. For a few NOCs,
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Cancer and the Environment: Gene-Enviroment Interaction the risk is multiplied when the exposure occurs in utero. The fetus, of course, is growing rapidly and, for that reason, is likely to be more susceptible to some carcinogens. It is also possible that a mother’s or father’s diet before the child’s conception could play a role, presumably by changes in the DNA of the sperm or the egg that would then lead to increased risk. Human exposure to NOCs is widespread; these compounds have been detected in many common exposures and products, including cigarette smoke, automobile interiors, and cosmetics. In addition to being exposed to NOCs, humans are also exposed to precursors that combine to form NOCs in the gut and elsewhere in the body. In fact, most human exposure is thought to occur via synthesis in the body from precursors. Some substances, such as vitamins C and E, inhibit the formation of NOCs from precursors and protect animals from developing NOC-induced tumors. Diet is a major source of NOCs, NOC precursors, and NOC inhibitors. Meats cured with nitrite, such as hot dogs and luncheon meat, contain NOCs and NOC precursors. Fruit, vegetables, and vitamin supplements contain NOC inhibitors. The NOC hypothesis predicts that a mother’s frequent eating of cured meats and infrequent eating of fruits and vegetables during pregnancy would increase the risk of brain tumors in her children. Studies done to date generally support the hypothesis that frequent eating of cured meats during pregnancy increases the risk of such tumors and provide limited support for a protective effect of fruits and vegetables. However, individuals who eat a lot of cured meats might also have a diet high in fat, and that high-fat diet—rather than cured meats—could be responsible for the increased risk. Similarly, eaters of cured meats may have diets low in folate, which could increase the risk. The most common childhood cancer, leukemia, has not been well studied in relation to diet, said Bunin. Although NOCs have not been linked to leukemia in animals, because of their potency as carcinogens in general and the ability of some of them to act transplacentally, a few studies have looked at foods with NOCs in relation to leukemia. A hypothesis has been proposed regarding the development of leukemia in the first year of life. In a majority of infant leukemias, the leukemic cells have abnormalities in band q23 of chromosome 11. Leukemias that occur after cancer treatment with epipodophyllotoxins, a class of chemotherapeutic agents, also have 11q23 abnormalities. These chemotherapy drugs inhibit an enzyme called topoisomerase II (Topo II) and increase the risk of leukemias with 11q23 abnormalities. If epipodophyllotoxins inhibit Topo II and increase the risk of leukemias with 11q23 abnormalities, perhaps other inhibitors of this enzyme also increase the risk of the same leukemias. Other inhibitors of Topo II exist in nature and include certain flavonoids and medications. Some investigators have postulated that maternal exposure to Topo II inhibitors during pregnancy increases the risk of leukemias with 11q23 abnormalities in infants. In a preliminary study, said Bunin, no association between foods
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Cancer and the Environment: Gene-Enviroment Interaction containing these inhibitors and infant leukemia overall was observed. However, when the two subgroups of infant leukemia—acute lymphocytic leukemia and acute myeloid leukemia—were analyzed separately, strong and significant associations were seen for the myeloid leukemia but not for the lymphocytic leukemia. Research linking diet and childhood cancers has been limited to brain tumors and leukemia. For most other childhood cancers, no studies have investigated the role of diet, said Bunin; thus, additional research on other childhood cancers may detect new risk factors. SUMMARY Years of research have resulted in a number of advances in the prevention and treatment of cancer, leading to an increase in survivorship across many cancers. While these results are promising, some researchers and community leaders have questioned whether the results are universal for all areas of our populations. Special populations such as migrant farmworkers, children, immigrants, and ethnic groups will have to be included in future research to ensure that they are also able to benefit from the new advances in research. Further understanding of environmental exposures in various subgroups through longitudinal studies will be necessary to more carefully identify risk in these groups, according to some participants.
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