Environment vs. Genes

Unlike the chicken-and-egg dilemma, scientists know that genes come before the environment. In genetically based diseases, however, the question is not when but how. How do environmental conditions and lifestyle choices interact with a person's molecular structure? "We're all groping in the dark to find out how to get a handle on this complexity," says Marianne Berwick, an epidemiologist at Memorial Sloan-Kettering Cancer Center, New York. Although scientists can now assess exposure levels to toxic agents and examine the body's response to those toxins through the presence of DNA variations known as biomarkers, finding the trigger point, or points, for disease onset is far more difficult. "Pure, genetically caused disease represents five to 10 percent of the disease burden in the United States; the rest is linked to a combination of multiple factors, both genetic and environmental," says Samuel Wilson, deputy department head, National Institute of Environmental Health Sciences (NIEHS). "Nutrition and lifestyle are huge factors, so we're trying to understand the linkages, including nutrition and lifestyle, in the context of molecular events occurring in cells that lead to the tissue changes characteristic of disease." The environment-gene link is especially true with cancer. "The overwhelming evidence is that the environment is involved in the vast majority of cancers," says Neil Caporaso, a physician and chief of the pharmacogenetics section at the National Cancer Institute. "If you look at countries where cancer incidence is high and [others] where incidence is low, you can find 10-, 50- and 200-fold differences. It's hard to explain that in terms of heredity, but relatively easy to explain in terms of environmental exposures. Premise number one now is that most cancer is caused by the environment." The blueprint for studying cancer in relationship to the environment is changing from reductionist models, which look at one or two variables and a few genes, toward a complexity theory, which examines multiple systems' interactions.1 Proving direct correlations between genetic and environmental factors, even with the use of high-powered statistics, is "really hard to do," says Irene Eckstrand, an evolutionary biologist and health science administrator at the National Institute of General Medical Sciences, which also funds large population genetics and genetic epidemiology studies. "The hope is to be able to identify which elements of the environment and genetics put you at risk," she explains. Science is finding new tools to help. Last year, NIEHS launched the $10 million National Center for Toxicogenomics, which coordinates international research in this field. Toxicogenomics attempts to explain how the entire genome is involved in biological responses to toxicants and stressors. Toxicogenomics measures specific changes in gene expression, species to species, as a result of exposure to drugs and other environmental agents, and provides a genetic snapshot of individuals' unique susceptibility to cancers and other diseases. These studies involve microarray/mRNA hybridization technology and analyses of massive amounts of single nucleotide polymorphisms (SNPs) and other sequencing data using bioinformatics tools.2 SNPs and other variations in genetic material actually provide a unique signature of whole genome response to toxicity, pinpointing the agent and dose to which individuals and even entire populations have been exposed. The goal, Wilson explains, is to stimulate population-based research that applies toxicogenomic findings to the clinical setting in hopes of detecting and managing early stage disease or preventing its onset. "The new information and attendant technologies surrounding the sequencing of the human genome represent a real challenge in the way environmental health science will be done into the future," Wilson says. That change, he suggests, represents a departure from standard in vitro assays and animal models with limited applicability to human toxicity research. "We get much more diversified information [enabling us] to examine expression patterns we could not decipher before."1 At the NCI, Cancer Genome Anatomy Project researchers have found about 40,000 new genes. Because DNA sequencing exponentially increased the pace of gene identification, scientists can determine which genes are active in normal or in cancerous tissues. Another NCI-funded project quantifies cancer risks associated with specific environmental and genetic factors--for example, a meta-analysis of the interaction between smoking, bladder cancer and a polymorphism in N-acetyltransferase-2, a gene involved in the metabolism of several carcinogens.3 More traditional research projects are going on as well. NCI's Division of Cancer Control and Population Sciences has funded several large cohort and interdisciplinary studies looking at the genetic epidemiology of cancer.4 One research project headed by Berwick models genetic susceptibility to melanoma, looking at the role of sun exposures and mutations of three gene classes, which have different functions in determining cancer risk: the cell cycle genes CDKN2A and CDK4, nucleotide excision repair genes, and genes relating to cutaneous pigmentation. The study will ultimately involve 3,500 subjects, who will provide extensive DNA samples and answer environmental questionnaires so researchers can look at genes and different levels of environmental exposures. "If we don't measure environmental exposure, we'll still be left with mud in the end," Berwick says. There's much to learn, she says, such as how to standardize the research and find an overall measure of DNA repair capacity. "If we can measure some polymorphisms in the repair genes, this will give us some insight," Berwick says. "Before, we used to think there were distinct repair pathways; however, we know now that the different repair enzymes compete for lesions so they can repair them; and nucleotide excision repair is involved in base excision repair, so it's very complicated. Our hope is that by more complex mathematical modeling, we'll be able to draw associations between different SNPs, and through the indirect approach, we can come to understand what is important." But the paradigms for biomathematical approaches are still rudimentary, Berwick says. Scientists now believe a genetic predisposition toward melanomas combined with environmental exposure causes the actual cancer. "But once we understand the more subtle genetic factors such as the effects of the DNA repair gene polymorphisms or the pigmentary gene polymorphisms, as well as other factors, I think we can learn to prevent melanoma," she says. "Once we understand the mechanism of how it occurs, we'll be in a much better position to [develop therapies and] prevent people from dying from it." Other NCI-funded research is happening at the University of Southern California and the Mt. Sinai School of Medicine in New York. Researchers are examining the risk of breast cancer and radiation sensitivities in families with the ATM gene, which codes for the mutated protein that causes ataxia telangiectasia. The study provides an empirical basis for estimating cancer risk in ATM heterozygotes and assesses the interactive role of ATM and radiation in the cause of breast cancer. NCI also funds investigations of genetic interactions with smoking, bladder and lung cancer, gene-hormonal interactions in ovarian cancer, and the molecular epidemiology of co-lorectal cancer, among many others. In multifactorial research on lung cancer and smoking, Caporaso and colleagues will look at several hundred genes involved in activating and deactivating carcinogens and nicotine, including CYPA26, the gene responsible for the P450 enzyme that metabolizes nicotine. "One of the very interesting and complicated things is that we realize that not only is cancer influenced by genetics, but smoking itself is dramatically influenced by genetics," he says. Although peer influence is a factor, a person's likelihood of becoming addicted is genetically controlled, he says. "Some people have an adverse reaction to a few cigarettes ... while others are easily hooked." Caporaso postulates that nicotine dependency could be tied to a deficit of dopamine receptors in the brain. "We've identified some genes that are potentially implicated in nicotine addiction," he says. So, while the environment contributes a dangerous chemical, it's the body's hereditary machine that ultimately decides whether cancer will grow. "The enzymes that activate or eliminate carcinogens are under hereditary control and differ widely among the population." Arielle Emmett can be contacted at arielleem@snip.net. References 1. K. Olden, and S. Wilson, "Environmental health and genomics: visions and implications," Nature Reviews: Genetics, 1:149, 2000. 2. National Center for Toxicogenomics, "NCT Overview," www.niehs.nih.gov/nct/concept.htm. 3. P. Marcus, et al., "Cigarette Smoking, N-Acetyltransferase 2 Acetylation Status, and Bladder Cancer Risk: A Case Series Meta-analysis of a Gene-Environment Interaction," Cancer Epidemiology & Prevention, 9:461-7, 2000. 4. National Cancer Institute, Epidemiology & Genetics Research Program, Division of Cancer Control & Population Sciences, http://dccps.nci.nih.gov/.

Environment vs. Genes

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