5
Gene–Environment Interaction in Site-Specific Cancers

Through many years of fundamental research, we have begun to have a better understanding of cancer. Research underlying the basic phenomenon has been hampered by the fact that “cancer” is not a singular disease, but rather a closely linked group of molecular disorders. These disorders vary in their etiology and mechanisms but have some common intersections. By understanding the differences and similarities in cancers from various body sites (e.g., breast, prostate), we can continue to make advances in cancer research.

The role of the environment has been actively investigated in many site-specific cancers during the last century. Through the use of epidemiology, the advent of molecular biology, and advances in computer technologies, investigators are now able to answer more sophisticated questions than would have been possible 30 years ago. Large cohort studies are now able to be conducted to answer questions on a population level and also to probe research within a subgroup of individuals. This chapter covers some of the recent advances in understanding the relationships between genes and the environment in site-specific cancers, including breast, lung, colorectal, and prostate cancer, as described by various presenters.

BREAST CANCER

It is estimated that 184,200 women in the United States will be diagnosed with breast cancer this year. This is reflected in the high incidence rates observed for many racial–ethnic groups, both internationally and nationally. In the past 15–20 years, researchers have shed light on the etiology and risk factors involved in breast cancer, including reproductive hormones, genetic factors, and environmental factors. By exploring these complex interactions, researchers may be able to develop additional strategies to reduce the incident rate of breast cancer.



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Cancer and the Environment: Gene-Enviroment Interaction 5 Gene–Environment Interaction in Site-Specific Cancers Through many years of fundamental research, we have begun to have a better understanding of cancer. Research underlying the basic phenomenon has been hampered by the fact that “cancer” is not a singular disease, but rather a closely linked group of molecular disorders. These disorders vary in their etiology and mechanisms but have some common intersections. By understanding the differences and similarities in cancers from various body sites (e.g., breast, prostate), we can continue to make advances in cancer research. The role of the environment has been actively investigated in many site-specific cancers during the last century. Through the use of epidemiology, the advent of molecular biology, and advances in computer technologies, investigators are now able to answer more sophisticated questions than would have been possible 30 years ago. Large cohort studies are now able to be conducted to answer questions on a population level and also to probe research within a subgroup of individuals. This chapter covers some of the recent advances in understanding the relationships between genes and the environment in site-specific cancers, including breast, lung, colorectal, and prostate cancer, as described by various presenters. BREAST CANCER It is estimated that 184,200 women in the United States will be diagnosed with breast cancer this year. This is reflected in the high incidence rates observed for many racial–ethnic groups, both internationally and nationally. In the past 15–20 years, researchers have shed light on the etiology and risk factors involved in breast cancer, including reproductive hormones, genetic factors, and environmental factors. By exploring these complex interactions, researchers may be able to develop additional strategies to reduce the incident rate of breast cancer.

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Cancer and the Environment: Gene-Enviroment Interaction Reproductive Hormones During the 1990s, a series of landmark prospective epidemiologic studies were published showing that a very important and reliable predictor of breast cancer risk is the amount of circulating estradiol in the blood of both pre- and postmenopausal women. In fact, this is the best single predictor of risk, said Brian Henderson, University of Southern California. How this risk factor accounts for increased risk of breast cancer is a subject of intense research. A very important and reliable predictor of breast cancer risk is the amount of estradiol in the blood of both pre- and postmenopausal women Brian Henderson Henderson described a long-standing focus on the role of sex steroids in the etiology of breast cancer, especially related to stimulation of the breast by estrogen and, more recently, progestin. This focus has been driven by the premise that estrogen and progestin are the primary determinants of cell proliferation in breast epithelium and that cell proliferation is a prerequisite for many of the genetic changes necessary for cell transformation to a malignant phenotype. The strong and consistent association between a woman’s menstrual history and breast cancer risk implicates lifetime exposure to sex steroid hormones as a major factor in the causation of breast cancer. Recent epidemiologic studies have implicated estrogens more directly, by showing that circulating levels of the biologically most potent estrogen, estradiol (E2), are significantly higher in breast cancer patients compared to normal controls. Moreover, said Henderson, plasma estrogen levels differ by racial–ethnic group and these differences appear to contribute to racial–ethnic variation in breast cancer rates. In addition, exogenous exposure to these steroids, as combined estrogen and progestin replacement therapy, also substantially increases the risk of breast cancer. In addition to the level of circulating hormones, the role of hormone replacement therapy and the age at menarche and fecundity also have a relationship to breast cancer. For example, in the late nineteenth century in Europe and the United States, there was a pattern of a late age at menarche, a short period of fecundity, and an early onset of menopause. By the early twentieth century, the age of menarche had decreased and the length of fecundity increased, not only in the West but elsewhere in the world, including post-World War II Asia. This has coincided with a dramatic increase in breast cancer rates over the last 50 years. The use of multiethnic cohort studies will begin to address the complex interplay between genetic and environmental risk factors according to Henderson. To further understand these risk factors, Henderson and others have turned to genetics. The process of breast cancer is driven by ovarian steroid hormones, mainly estradiol and progesterone, and these result from a biosynthetic pathway that involves a series of enzymes encoded by genes (see Figure 5-1). It is in these

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Cancer and the Environment: Gene-Enviroment Interaction FIGURE 5-1 Estrogen biosynthesis pathway. SOURCE: B. Henderson (2001). Reprinted with permission. genes that scientists have been looking for genetic variation that might explain differences in the amount of circulating estradiol, which can vary substantially from one woman to the next. This sort of variation is certainly consistent with the multigene model, said Henderson, so investigators have tried to express the risk of breast cancer—most easily represented by cumulative exposure to endogenous estrogen and progesterone—in terms of multiple susceptibility genes, contributing to build a multigenic model that separates women into high- and lowrisk groups. By coupling epidemiologic research with other genetic studies, we will begin to build models of breast cancer susceptibility. Breast Cancer Genetics Breast and ovarian cancer appear to be coinherited in families. Breast cancer is thought to be caused by spontaneous mutations in somatic cells or by germline inheritance of mutations in breast cancer susceptibility genes. Approximately 30 percent of women who present with a diagnosis of breast cancer have at least one relative who has had cancer. One such gene, the BRCA1 gene, was identified in 1990 by Mary-Claire King and her group and then cloned in 1994. BRCA2 was identified and cloned in 1995. Germline mutations in the BRCA1 or BRCA2 susceptibility genes result in breast cancers characterized by young age of onset, bilaterality, association with ovarian cancer and other tumor types, vertical transmission, and distinct tumor phenotypes. Many investigators have tried, so far unsuccessfully, to explain the functions of BRCA1 and BRCA2 and why they might be relevant to breast cancer. They probably function to maintain genomic stability and serve as tumor suppressor genes. However, there are multiple roles that these genes play

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Cancer and the Environment: Gene-Enviroment Interaction in the cell specifically (e.g., scaffold protein involved in oxidative DNA repair), and it is not clear why they are so highly penetrant for breast and ovarian cancer, said Olufunmilayo Olopade, of the University of Chicago. Testing for the presence of BRCA1 and 2 mutations is now offered to women who have a family history of breast and ovarian cancer and are over the age of 18. Specific mutations have been identified in Caucasian and African American families, and some families have unique mutations, seen only in their family lineage. In some cases, the significance of mutations is hard to discern, so testing is not always clinically useful, said Olopade. What is known is that in families with BRCA1 mutations, the average age of cancer onset tends to be very young. With BRCA2, the mean age of onset is a little older than with BRCA1, and in one study by Olopade, there was a significant proportion of postmenopausal breast cancer that could be attributed to germline mutations in BRCA2. Not everyone who inherits a mutation in the BRCA genes develops cancer. There are, in fact, other genetic and environmental factors that affect penetrance, and some of these factors may be modifying genes that are inherited by different populations at different rates. For example, hormonal reproductive factors and response to DNA damage affect risks, and some studies actually indicate that smoking reduces breast cancer risk in BRCA carriers. This does not suggest that these women should smoke, said Olopade, but it does suggest that there are issues of carcinogen metabolism and other enzyme activity that have to be considered. Olopade noted that there is a clear distinction between BRCA1 and BRCA2 tumors. BRCA2 tumors tend to be estrogen receptor (ER) positive, whereas BRCA1 tumors are mostly ER negative and highly proliferative. This may have implications for prevention, said Olopade, because antiestrogen therapy with tamoxifen can reduce the incidence of ER-positive breast cancer. “If you can get a 50 percent reduction in breast cancer risk through hormonal ablation or through tamoxifen use, then you can imagine how you might be able to prevent some of these BRCA2 tumors,” said Olopade. A lot of work needs to be done in terms of understanding how environmental factors influence the development of cancer and then how these individuals respond to different therapies, she concluded. These examples illustrate the clinical value of addressing the genetic basis of cancer and the importance of understanding genetic mechanisms in developing methods of cancer prevention, early detection, and targeted therapies. Other genetic factors have been examined in addition to BRCA1 and 2. For example, several years ago, Kari Hemminki described a variant of the gene for cytochrome P-450, a key enzyme in the initial stages of sex steroid biosynthesis. He suggested that the C allele upregulated the gene and, therefore, would lead to more estrogen production. Subsequent studies showed that this allele appears to be associated with an increased risk of breast cancer, particularly with more regional or distant metastatic breast cancer than disease limited to the breast. This led to a hypothesis linking a genetic basis for greater lifetime estradiol

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Cancer and the Environment: Gene-Enviroment Interaction secretion with a higher risk of breast cancer. Henderson noted that more research is needed that looks at other parts of genetic pathways, for example, growth factor genes, hormone receptors, and other similar enzymes along the same pathways of biosynthesis or metabolism. Environmental Factors There has long been an assertion by the general population that environmental factors play a role in the generation of breast cancer. This has been fueled in part by the observation that established risk factors for breast cancer do not fully explain breast cancer risk. During the workshop, this was one of the more controversial topics discussed by researchers. According to Mary Wolff of the Mt. Sinai School of Medicine, researchers have been investigating issues surrounding lifestyle (including diet), obesity, and adverse exposures in an attempt to identify suceptible factors in initiating breast cancer. Unlike the senario for lung cancer where there is strong agreement between researchers that smoking is a risk factor for developing cancer, the role of environmental factors in breast cancer is not as clear. Is there a role for the environment in breast cancer? The research is incomplete at this time according to many researchers. Investigations into pesticides such as DDT and DDE have not shown a consistent association with breast cancer (Snedeker, 2001). Diet and obesity may play a role in breast cancer development since they both contribute to changes in circulating hormone levels and age at menarche—all known risk factors for breast cancer. Further, one sees a change in incidence rates as ethnic groups shift to a more Western lifestyle (e.g., decrease in age of menarche, use of hormone replacement therapy)—for example, the increase in the incident rate of cancer in Asian women born in the United States compared to those living in Asia. Understanding the complex interactions of lifestyle, diet, established risk factors, and genetics will continue to be an important area of research. LUNG CANCER Molecular and Environmental Bases of Lung Cancer There are approximately 160,000 new cases of lung cancer every year in the United States, and at least 80 percent of those people will die within five years of diagnosis. This results in more deaths from lung cancer in both men and women than from any other specific cancer. There are about 47 million current smokers and 44 million former smokers in the United States. Both groups are at increased risk of developing lung cancer, although current smokers have the higher risk. Less than 20 percent of long-term smokers develop lung cancer by age 75, and we must develop ways to identify these people at an early stage of cancer

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Cancer and the Environment: Gene-Enviroment Interaction development to improve the cure rate, said John Minna. One possibility may be by genetic epidemiology. Genetically determined factors that abrogate the effects of environmental carcinogens may explain differences in susceptibility, said Margaret Spitz, of the M.D. Anderson Cancer Center. The challenge in risk assessment is to account for this interindividual variation in susceptibility to carcinogens. Evidence of familial aggregation of lung cancer provides indirect support for the role of a genetic predisposition to lung cancer. These studies of patterns of inheritance suggest that a small proportion of lung cancer is due to “lung cancer genes” that are probably of low frequency but high penetrance. Less than 20 percent of long-term smokers develop lung cancer by age 75. John Minna Lung cancer risk from smoking is dependent on the dose of tobacco carcinogens, which is modulated by genetic polymorphisms in the enzymes responsible for carcinogen activation and detoxification, as well as by the efficiency of the host cells in monitoring and repairing DNA damage due to tobacco carcinogens. Individuals with susceptible genotypes (or adverse phenotypes) tend to develop lung cancer at earlier ages and with lower levels of tobacco exposure. On the other hand, the genetic component of risk tends to be lower at high-dose levels, when environmental influences overpower any genetic resistance. By studying polymorphisms in DNA repair genes, Spitz and others are trying to establish genotype–phenotype correlations in the context of environmental insults. For example, by correlating polymorphisms in a DNA repair gene with the functional DNA repair assay, one can determine if markers in surrogate tissues reflect molecular events in the target lung tissue. Genotype–phenotype and diet–gene interactions are also being actively studied. The gene that controls glutathione S-transferase activity, which is a protective detoxifying mechanism, is being studied intensively. The genotypes for these protective genes differ among various ethnic and racial groups. In general “null genotypes,” those with little to no activity, have been shown to be associated with increased risk, but results have varied. To explain the inconsistencies in the results, Spitz and others have tried to estimate the significance of other unmeasured or unidentified covariates. They examined factors in the diet, specifically isothiocyanates, which are nonnutritive compounds found in the Brassica family of vegetables such as brussels sprouts, broccoli, and cabbage. These compounds are known to be very effective inhibitors of tumor formation in animal model systems, and many case-control and cohort studies have consistently shown an association between consumption of greater amounts of these vegetables and protection against the development of lung cancer. Other studies have used “reporter genes” to measure the extent of DNA repair in cells transfected with carcinogen-damaged plasmids. “We know that DNA repair capacity declines with advancing age, however, the youngest cases

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Cancer and the Environment: Gene-Enviroment Interaction seem to have the poorest DNA repair capacity,” said Spitz. Women have significantly poorer repair capacity than men, and the longest-term smokers have the best DNA repair capacity, perhaps as an adaptation to long-term smoking. Many of the markers are relevant not only for risk assessment but also for predicting response to chemo- and radiation therapy. Thus, individuals on chemotherapy regimens who have good DNA repair capacity actually do worse because they are more likely to remove the therapeutic agent that causes damage to cancer cells. We know that DNA repair capacity declines with advancing age, however, the youngest cases seem to have the poorest DNA repair capacity. Margaret Spitz The true dimensions of gene– environment interactions probably depend on multiple susceptibility factors, concluded Spitz. In the near future, micro-array technology will enable the performance of large-scale, low-cost genotyping. The resulting ethical, educational, social, and informatics considerations will be challenging. However, the ability to identify smokers with the highest risks of developing cancer will have major preventive implications for intensive screening and smoking cessation interventions and for chemoprevention trials. Molecular Pathogenesis of Lung Cancer John Minna of the University of Texas Southwestern Medical Center and other investigators have hypothesized that clinically evident lung cancers have accumulated 10–20 different genetic abnormalities in dominant oncogenes, or tumor suppressor genes. If this is true, it may be possible to discover carcinogen-exposed respiratory epithelial cells with only a subset of these changes and to intervene at an early stage with treatment or chemoprevention. Similarly, it is also hypothesized that these changes are recurrent and common among different tumors, and this may have implications for directing the search for specific diagnostic and therapeutic targets. Many studies have been published on the search for genetic abnormalities in lung cancer. However, with few exceptions, these studies have not been global in nature, either in testing for genome-wide abnormalities or in testing for multiple abnormalities in the same individual lung cancer. There are four major histologic types of lung cancer, and there are acquired genetic differences among these types. The general mechanisms that underlie their pathogenesis are similar; thus, it is important to identify the molecular changes that lead to these cancers. If 20 different changes are required for a lung cancer to develop, smoking-damaged respiratory epithelial cells could in theory be detected with only a few changes, allowing an early molecular diagnosis of lung cancer or prediction of which people are most likely to develop it.

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Cancer and the Environment: Gene-Enviroment Interaction Allelotyping—in this instance, comparing tumor and normal tissue for genetic change involving loss of one of the parental alleles—is one way to look for genetic changes. Minna and colleagues find that multiple small clonal or subclonal patches containing molecular abnormalities are present in histologically normal or slightly abnormal bronchial epithelium of patients with lung cancer and people who smoke cigarettes. In detailed studies of bronchial epithelium and bronchial biopsies from current or former smokers without lung cancer, they also found thousands of clonal patches showing allele loss in histologically normal-appearing respiratory epithelium. These patches can be detected more than 30 years after cessation of cigarette smoking, suggesting the potential for damaged stem cells to repopulate. Small cell lung cancer (SCLC) has many morphological and biochemical features that distinguish it from non-small-cell lung cancer (NSCLC) histologic types, said Minna. These distinctions are of diagnostic importance and commit patients with different histologic types to different initial treatment regimens. With the exception of bronchoalveolar lung cancer, smoking and tobacco carcinogens are the major underlying etiologic factors. Clearly, SCLC etiology is strongly tied to cigarette smoking. Thus, the smoking-damaged, histologically normal epithelium associated with SCLC appears “genetically scrambled” and has incurred significantly more damage than the epithelium accompanying NSCLC. Minna concluded that SCLC and NSCLC do not differ significantly in the number of their genetic alterations. However, they do differ in the kinds of specific genetic alterations that occur. In addition, the smoking-damaged bronchial epithelium accompanying SCLCs appears to have undergone significantly more acquired genetic damage than that seen in NSCLCs. Minna called for studies to identify the specific genes involved at these multiple sites and to determine whether these provide new tools for early molecular detection, monitoring of chemoprevention efforts, and identification of specific targets for developing new therapies. COLORECTAL CANCER Risks for Colorectal Cancer Colorectal cancer remains the third leading cause of cancer deaths in each sex and the second leading cause overall in the United States. Despite the fact that this disease is often preventable by screening, there are 130,000 new cases and about 55,000 deaths each year. Colorectal cancers arise primarily in adenomas. Because adenomas are usually asymptomatic, they are not readily detected. The prevalence of these lesions increases with age and is greater in men than women. Autopsy studies suggest that one-fifth to three-fifths of individuals have prevalent adenomas, and screening studies of average-risk populations have found that one-fourth to two-fifths of individuals have adenomas.

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Cancer and the Environment: Gene-Enviroment Interaction An important environmental role in the development of colorectal cancer is suggested by the variance in incidence of the disease. Moreover, there is a twentyfold variation in incidence rates in different geographic regions around the country, indicating that genetic, environmental, and lifestyle factors play a role in etiology. Because adenomatous polyps are precursors to colorectal cancer, assessing the effect of environmental and genetic factors in adenoma occurrence and recurrence might help identify relatively asymptomatic individuals who are at increased risk of cancer and who would benefit most from public health interventions. Certain populations and individuals with particular genetic syndromes inherit germline mutations that increase the risk of colorectal cancer. The genetic basis for the development of colorectal cancer involves the accumulation of specific somatic mutations in proto-oncogenes and tumor suppressor genes with increasing age, said Raymond DuBois of the Vanderbilt University Medical Center (Figure 5-2). However, only a small proportion of colorectal cancers are attributable to inheritance of these rare, highly penetrant mutated genes. It is also evident that variability in carcinogen-metabolizing genes influences the risk of colorectal cancer. These polymorphisms can be very common, such that even modestly increased relative risks may account for a higher popu- FIGURE 5-2 Incidence of colorectal cancer versus age. SOURCE: SEER (1992–1996). The SEER program collects and publishes cancer incidence and survival data from 11 population-based cancer registries and 3 supplemental registries covering approximately 14 percent of the U.S. population (see http://seer.cancer.govformoreinformation).

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Cancer and the Environment: Gene-Enviroment Interaction lation-attributable risk than that due to highly penetrant, but rare, genetic mutations. Epigenetic changes, such as alterations in DNA methylation and gene expression, also may play a critical role in the development of this malignancy. These alterations are important in both inherited syndromes such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer and in sporadic tumors. It will be important to understand the roles of environmental exposure and host susceptibility to develop better screening, prevention, and treatment strategies, said David Alberts of the Arizona Cancer Center. Susceptibility to colorectal cancer is related to interindividual variability in biotransformation of endogenous and exogenous substances, as well as in DNA repair and cell cycle control, according to Alberts. Genetic variation may increase susceptibility by altering the rates of activation and detoxification of carcinogens. In the future, risk assessment has to factor in susceptibility to certain classes of carcinogens in subpopulations. Interactions between specific polymorphisms in a metabolism gene and environmental exposures provide evidence that the gene substrate is a component relevant to colorectal cancer etiology or prevention. Environmental factors may interact with metabolic genetic polymorphisms via a model in which the exposure alone, but not the variant genotype alone, increases disease risk, and exposure interacts with the variant genotype to further increase risk in exposed individuals. The same interaction can also modulate disease pathogenesis, in that exposure and susceptibility factors may alter the effects of other risk factors. Classification of subgroups of the population into those who may be more vulnerable to the effects of certain carcinogens may also have important implications beyond risk assessment. Through the identification of an increased risk in certain subgroups, disease risk factors may be better defined. However, to date, sample sizes for most studies attempting to uncover gene–environment interactions have been small, said Alberts, which limits the potential for detecting significant findings. Consumption of folic acid supplements, after a period of 15 or more years, may decrease risk of colon cancer by about 75 percent. David Alberts Alcohol consumption and tobacco smoking are known to increase the risk of colorectal cancer. Other studies have found an increased risk of colorectal cancer recurrence with alcohol consumption. Increased physical activity, dietary supplemental calcium intake, dietary iron intake, and hormone replacement therapy (for women) are all associated with a decreased risk of colorectal cancer. The role of a diet rich in fruits and vegetables in reducing this type of cancer is controversial. Further research will be needed to resolve this issue. In addition, the chronic use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a 40–50 percent reduction in risk. Al-

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Cancer and the Environment: Gene-Enviroment Interaction though the pathways by which anti-inflammatories inhibit cancer growth are unknown, research efforts have focused on understanding the molecular basis for the chemoprotective effects associated with the use of NSAIDs. The activity of the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) is inhibited by NSAIDs. Some researchers have reported an increase in COX-2 levels in a number of solid tumors, which suggests that this enzyme may serve as a molecular target for cancer prevention. Further, recent clinical studies indicate that the presence of COX-2 in human lung and colon cancers is associated with a negative clinical prognosis. Therefore, COX-2 inhibitors are presently being evaluated for the prevention or treatment of several cancers in humans, said Alberts. Alberts also described an increasing body of epidemiological evidence from case-control and cohort studies supporting the role of folate in reducing the risk of colorectal cancer. Folate intake and blood levels have also been consistently associated with a lower risk of colon adenomas. Recent results indicate that the consumption of folic acid supplements, after a period of 15 or more years, may decrease the risk of colon cancer by about 75 percent. Additionally, these investigations suggest that alcohol consumption increases the risk of colorectal neoplasia by acting as a folate antagonist. If colorectal cancer is treated surgically while still localized, the outcome is quite good, with a survival rate greater than 90 percent. Therefore, early detection could save about 28,000 lives each year, said DuBois. Development and characterization of accurate markers for adenomas are needed because this could identify the highest-risk group of patients that might benefit from early detection with colonoscopy and other screening interventions. PROSTATE CANCER Prostate Cancer: Epidemiology, Hormones, and Diet Prostate cancer is the second leading cause of cancer deaths in men in the United States today. Currently, researchers have identified age as being one of the two most important risk factors for prostate cancer. Recent estimates by the National Cancer Institute suggest that one in four men has some cancerous cells in his prostate by age 50, which increases to one in two by age 80. Race–ethicity is the second most important risk factor for prostate cancer. In the United States, African American men have the highest incidence of prostate cancer, while Asian Americans and Latinos have the lowest incident rates (Ross et al., 1998). Interestingly, one sees that the international rates for prostate cancer in men and breast cancer in women are remarkably similar and seem to be determined primarily by the environment in which one lives, said Donald Coffey of the Johns Hopkins School of Medicine (Figure 5-3). This risk can vary by more than tenfold among countries. Traditionally, native Japanese and Chinese

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Cancer and the Environment: Gene-Enviroment Interaction FIGURE 5-3 Comparison of prostate and breast cancer in different countries. SOURCE: Griffiths et al. (2001). Reprinted with permission by CompGraphics Services, UK. men have the lowest incidence of prostate cancer. Similar to breast cancer, researchers have observed that migration can change a person’s risk. For example, Asians who immigrate to the United States have a greater incidence of prostate cancer than those living in Asia. However, their rates never reach the incident rates of Caucasian Americans. The differences between various incidence rates may be due to testosterone biosynthesis or metabolism (see Ross et al., 1998), as well as environmental influences, genetic control, or a gene–environment interaction. Further research will help to us to understand these differences. Hormones play a major role in the growth and function of the prostate gland including cellular growth and proliferation (Ross et al., 1998). For these reasons, hormones have attracted considerable research interest in cancer of the reproductive organs. Indeed, researchers have elucidated a role of hormones in both breast and prostate cancer. However, not all organs involved in reproduction have reported incidences of cancer. For example, there is little known risk for human seminal vesicle cancer. In addition, not all mammals have high rates of cancers. Only man and dog have been shown thus far to have a high naturally occuring incident rate of prostate cancer (Coffey, 1993). Some of the differences may be linked to the role of hormones in various organs. Androgen, estrogen, and progesterone receptors are present in prostate and in breast tissue, and cellular growth is driven by androgens or estrogens in either tissue, said Coffey. In the developing human, testosterone and androgen receptors inhibit breast development and induce the seminal vesicles. Studies in animal models have shown that hormonal treatment influences prostatic growth. Dihydrotestosterone and the androgen receptor induce prostate growth. Estrogens depress androgen production and depress prostate growth, whereas estrogens plus dihydrotestosterone enhance pros-

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Cancer and the Environment: Gene-Enviroment Interaction tate growth. Understanding and characterizing the differences between organs may help to understand the mechanisms underlying prostate cancer. The question remains whether genetic or environmental factors may play a role in the development of prostate cancer. Research is still going on in this area; however, factors that alter the hormonal environment may have an effect on the incidence of cancer. Similar to breast cancer, dietary factors are hypothesized to influence prostate cancer. An association has been reported between prostate cancer and fat intake. Dietary fat is converted by the body to androgens, which may stimulate the growth of prostatic cancer cells. Men who eat high-fat diets have a higher rate of prostate cancer than those who adhere to diets low in fat and rich in yellow and green vegetables. Researchers are continuing to investigate the interplay between hormones, genetics, and the enviroment to develop a more complete picture of prostate cancer. Herbal Therapies Alternative medicine including the use of herbal therapies is an emerging area in the treatment of various diseases. Often, patients are looking for alternatives or complements to Western medicine. Some researchers have begun to investigate some of the herbal therapies to determine if there is a scientific backing for the claims. One such alternative, according to Robert DiPaola of the Cancer Institute of New Jersey, is PC-SPES, a commercially available combination of eight herbs used as a treatment for cancer of the prostate. Because other herbal medicines have estrogenic effects in vitro, DiPaola and colleagues tested the estrogenic activity of PC-SPES in yeast and mice and in men with prostate cancer. They assessed the clinical activity of PC-SPES in eight patients with hormone-sensitive prostate cancer by measuring serum prostate-specific antigen (PSA) and testosterone concentrations during and after treatment. In the men with prostate cancer, PC-SPES decreased serum testosterone concentrations, and in those and other patients, it decreased serum concentrations of PSA. The batches of PC-SPES studied contained estrogenic compounds that were distinct from diethylstilbestrol, estrone, and estradiol. Therefore, its use may confound the results of standard or experimental therapies or produce clinically significant adverse effects. “The question remains, Why is it that mild phytoestrogens or mild estrogenic compounds within these particular plants might have a preventive possibility in terms of animal models but yet stronger estrogens would induce cancer?” said DiPaola. His laboratory has fractionated PC-SPES and found certain fractions with greater activity, suggesting that there are multiple estrogens in this product. Component herbs, such as licorice root, have weaker phytoestrogens. Since poor quality control exists in the manufacture of these unstandardized herbal mixtures, chemical analysis will be important to identify the chemical compounds responsible for this activity.

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Cancer and the Environment: Gene-Enviroment Interaction SUMMARY The variation in cancer incidence among various population groups has long suggested a role for the environmnet in cancer development. The environmental hypothesis is further supported by shifting cancer incidences in migrant populations whose rates tend to approximate those of their current host country, by geographic differences in cancer rates within the United States, by the changing incidence of certain cancers over time, by ethnic–socioeconomic differentials, and by the epidemiologic evidence linking risks to a variety of lifestyle and other environmental exposures. Not long ago, the role of inherited susceptibility in human cancer was considered to be quite small. However, recent progress in identifying and characterizing highly penetrant, but relatively rare, susceptibility genes has furthered our understanding of genetic mechanisms and their role in cancer etiology. Further, the common polymorphisms of modifier genes that confer low relative and absolute risks, but high population-attributable risks in the presence of relevant environmental exposures, are becoming increasingly important to the public health burden of cancer. Many speakers discussed the evidence suggesting a role for the environment, for genes, and for their interactions. Cancers such as breast, lung, and colorectal, which were thought to lack an inherited component in the past, are being linked to a number of rare but highly penetrant mutated genes. As many speakers asserted, understanding and characterizing these genes will be an important area of research for the next decade. They further emphasized the need to combine epidemiologic techniques with molecular biology. Cancer involves changes in DNA. We will have to determine which changes are germline and which are somatic and how environmental influences alter the mechanisms of DNA repair and replication. Some conference participants identified several strategies for reducing the future incidence of and death from cancer, the most critical being the reduction of tobacco use by all segments of the population, since smoking causes an estimated 30 percent of all cancer deaths. Another strategy suggested by some speakers would be to increase the use of effective but currently underutilized cancer screening tools. Yet other strategies identified include developing and applying state-of-the-art diagnostic tests and treatments, as well as identifying and reducing health disparities across diverse populations. Behavioral change, perhaps the most challenging, but potentially the most effective strategy, should be a central element of a successful cancer prevention program regardless of genetic predisposition to cancer, said several speakers.