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Gene-Environment Interactionsby Vickie J. Williams and Dawn Chalaire
Every patient with cancer will at some point ask the question: “Why me? Why did I get cancer?” Some patients blame their lifestyle choices; others attribute their disease to fate or bad luck. As it turns out, the answer to the question could be said to lie somewhere in between. It has long been known that both heredity and environment play a role in cancer susceptibility. All cancers have a genetic component because they arise from the faulty genetic control of cell growth, and about 75% of the cancers diagnosed in the United States can be attributed in part to environmental factors such as tobacco use, diet, infectious diseases, excessive sunlight exposure, industrial chemicals, and ionizing radiation. For many years, genetic and environmental causes of cancer were considered and studied separately. Then research began to show that these factors work in concert, as codeterminants of cancer susceptibility. This realization that most cancers are caused by an interaction between genes and the environment represented a new paradigm in cancer risk assessment. “Although an element of chance is likely to play a role in the complex, multi-step process leading to cancer development, there is mounting evidence that genetic factors influence susceptibility to cancer-causing exposures,” said Margaret Spitz, M.D., professor in and chair of the Department of Epidemiology at The University of Texas M. D. Anderson Cancer Center. Genetic markers of cancer risk The Human Genome Project, which identified and sequenced the approximately 30,000 genes in the human body, provided researchers with a blueprint for studying the biologic components of diseases such as cancer and has propelled the science of molecular epidemiology. “Scientists now have a clearer picture of the composition of human DNA, which will facilitate epidemiologic studies of which genes contribute to cancer susceptibility,” said Sara Strom, Ph.D., associate professor in the Department of Epidemiology. Researchers with the Cancer Genome Project, a massive undertaking aimed at mapping the genetic mutations linked to cancer, are using the Human Genome Project’s gene-sequencing and high-throughput mutation detection techniques to identify the gene sequence variants and mutations critical to the development of human cancers. The interplay between genetic markers of cancer risk and environmental factors is also the focus of extensive research at M. D. Anderson. Here, clinicians, basic scientists, and epidemiologists collaborate to identify molecular biomarkers of individual risk by studying commonly occurring variations in genes related to carcinogen metabolism, DNA repair, cell cycle control, stress responses, and immunity. “Our objective is to identify markers of genetic susceptibility for evaluation in case-control studies,” said Dr. Strom. Their studies, emphasizing genetically determined differences in people’s responses to environmental agents, or interindividual variations in cancer risk, are being conducted in tobacco-related cancers, leukemia, colon cancer, melanoma, and other cancers. Gene-environment interactions in smoking-related cancers The most recognized disease outcome linked to gene-environment interactions is lung cancer. Epidemiologic and clinical studies clearly document that smoking is the leading cause of lung cancer, accounting for nearly 90% of these tumors. However, it is also well documented that only a fraction (about 15%) of long-term tobacco smokers will get lung cancer. These patients are genetically susceptible to the carcinogenic effects of tobacco. “The diversity of human beings is remarkable,” Dr. Spitz said. “The fact that some smokers develop lung cancer while others don’t suggests that there are differences among smokers in susceptibility to the cancer-causing compounds in cigarettes.” To date, no specific lung cancer gene has been identified; however, researchers, including Christopher Amos, Ph.D., professor in the Department of Epidemiology, have isolated a narrow region of about 50 genes on a segment of chromosome 6. This region was found in 52 families with strong family histories of cancers of the lung, throat, and larynx. The next step is to determine the exact gene or genes in this region that are associated with lung cancer. Individuals whose cells are unable to properly repair damaged DNA also may be at higher risk for lung cancer. DNA repair systems are designed to maintain the integrity of the genome by preventing the accumulation of DNA damage that can lead to cancer. Nucleotide excision repair is one pathway responsible for repair of genes damaged by tobacco carcinogens. Unfortunately, the same nucleotide excision repair pathway is involved in repairing the damage to cancer cells caused by treatment with the common chemotherapy drugs cisplatin and carboplatin. Researchers in the Department of Epidemiology hope that by studying the genes involved in DNA repair, they might be able to construct genetic profiles that could be used to individualize therapy and to better understand treatment response in lung cancer patients. Research is also under way in other smoking-related cancers. A study published earlier this year by Xifeng Wu, M.D., Ph.D., professor in the Department of Epidemiology, and her team analyzed the relationship between eight genetic variations that affect DNA repair, smoking, and bladder cancer. The researchers found that smoking had the greatest effect on bladder cancer risk among the factors studied. However, three of the gene variants could predict bladder cancer risk with high consistency. These results support the hypothesis that gene-gene and gene-environment interactions contribute to bladder cancer risk. Dr. Strom is co–principal investigator of another study that is examining how genetic predisposition and environmental exposures interact to determine susceptibility to acute myelogenous leukemia. “Inhalation of benzene, which is present in gasoline, polluted air, and cigarette smoke, can induce changes in the expression of some genes, and these changes cause leukemia in some people. However, certain genetic traits must be present for a person to be affected by these exposures,” said Dr. Strom. “This study will help determine how the presence of genetic markers combined with environmental exposures and cytogenetic factors can help us identify which individuals are at greatest risk for acute myelogenous leukemia.” Gene-environment interactions in other cancers Colon cancer includes among its variants one of the most common inherited cancer syndromes known, hereditary nonpolyposis colorectal cancer (HNPCC). People with mutations of MSH2 and MSH6, both on chromosome 2, and MLH1, on chromosome 3, are at increased risk of HNPCC. These may interact with environmental predictors of colon cancer, including obesity, low levels of physical activity, smoking, and alcohol consumption. Gene-environment studies that would confirm such interactions in colon cancer are sparse. Marsha Frazier, Ph.D., professor in the Department of Epidemiology, is studying modifier genes in a unique cohort of patients with documented HNPCC. Dr. Frazier and her colleagues have found that variants in the insulin-like growth factor-1 (IGF-1) gene are involved in colorectal carcinogenesis. Their study, published this year in the Journal of the National Cancer Institute, was the first to report that these variants, which are thought to increase the production of IGF-1, modify the risk of HNPCC and, for that matter, any hereditary form of cancer. The findings are consistent with studies from other groups showing that high levels of IGF-1 in the blood are associated with a higher risk of sporadic (non-hereditary) colorectal cancer. Combining what is learned about these IGF-1 variants with information about other genetic and environmental risk factors may improve risk prediction and allow earlier identification of individuals who are genetically susceptible to developing colon cancer. In melanoma, evidence for a gene-environment intersection is very strong. This disease has been shown to run in families, and a mutation in the CDKN2 gene on chromosome 9 is common in these families. The mutation, coupled with exposure to ultraviolet (UV) radiation and photosensitizing chemicals, substantially increases the risk for this cancer. However, how UV exposure from sunlight leads to the development of melanoma is not yet clear. The first large case-control study reporting an important role for faulty DNA repair in UV-induced DNA damage was led by Qingyi Wei, M.D., Ph.D., professor in the Department of Epidemiology. In a study of more than 300 patients with melanoma and matching cancer-free controls, Dr. Wei and his colleagues showed that inefficient repair of UV-damaged DNA is a risk factor for melanoma. These findings help explain the variations in susceptibility to sunlight-induced melanoma. In another case-control study, Dr. Wei’s group also compared in vitro chromosomal damage induced by UVB radiation in the lymphocytes of patients with nonmelanoma skin cancer, patients with melanoma, and cancer-free controls. Compared with controls, the lymphocytes of patients with nonmelanoma skin cancer, but not those with melanoma, were much more likely to have UVB-induced chromosomal damage. “Both of these studies were the largest of their kinds,” Dr. Wei said. “The first study showed that UV radiation damages DNA and increases the risk of melanoma. The second study showed that the mechanism of action was not at the chromosome level. This doesn’t mean that UV exposure isn’t important, it just means that UV radiation doesn’t cause damage at the chromosome level in melanoma. The bottom line is avoiding UV exposure is the best strategy for skin cancer prevention.” Looking to the future Research in the Department of Epidemiology will continue to focus on elucidating gene-environment interactions in cancer etiology and developing individualized risk prediction profiles. “The long-term goal is to more precisely answer the question of who gets cancer and recommend personalized prevention and treatment interventions,” Dr. Strom said. Identifying individuals or groups who are most susceptible to cancer may make it possible to recommend careful surveillance and early detection, behavior modification strategies, or chemoprevention interventions. In cases where the disease is already present, oncologists may be able to tailor treatments according to individual genetic profiles. “We may one day be able to answer the ‘why me’ question—‘why did I get cancer?’—and perhaps we might be able to prevent cancer from occurring at all,” agreed Dr. Spitz. “It won’t happen overnight, or even in my lifetime, but we’re definitely moving in the right direction.”For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, July/August 2007 issue:
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