Even though cancer can be considered both a genetic and environmental disease, 50 years of epidemiologic research suggests that the vast majority of cancer is caused by environmental and lifestyle exposure to tobacco smoke, alcohol, viruses, drugs, and radiation.
Now, scientists are studying specific geneenvironment interactions that contribute to cancer risk. The strategy is to try to find specific gene alterations involved in the well-established pathways linking an exposure to a particular cancer, such as sun and melanoma, hormones and breast/prostate cancers, and tobacco smoke and lung/bladder cancers.
In contrast to alterations found in cancer-prone families, such as BRCA1/2 and APC, mutations in some of the genes now being studied are present in a large proportion of the general population and are thought to confer a relatively small increase in cancer risk. Two groups presented their findings at the recent annual American Association for Cancer Research meeting in San Francisco.
Bladder Cancer and Smoking
In a meta-analysis of 16 bladder cancer studies, researchers from the National Cancer Institute analyzed the interaction between smoking and a polymorphism in NAT2 (N-acetyltransferase-2), a gene involved in the metabolism of several carcinogens. NAT2 codes for an enzyme that detoxifies aromatic amines, compounds known to be potent bladder carcinogens present in tobacco smoke.
Although the link between bladder cancer and smoking is well established (it is estimated that cigarette smoking accounts for about half of the bladder cancer cases in men and for about 30% in women), researchers found that the relationship between cigarette smoking and bladder cancer risk was about 30% stronger among people with a particular polymorphism in NAT2 compared with those without the alteration.
People with the alteration are called slow acetylators; those without are considered rapid acetylators. About 55% of populations with European ancestry, 35% of African descent, and 15% of Asian descent have the alteration.
Pamela Marcus, Ph.D., and Nathaniel Rothman, M.D., from NCIs Divisions of Cancer Prevention and Cancer Epidemiology and Genetics found that compared with nonsmokers without the alteration (rapid acetylators), smokers without the alteration have about a twofold increased risk, whereas smokers with the polymorphism have about a threefold increase in risk. The population attributable risk for smoking in the predominantly male European population in this analysis was 35% for slow acetylators versus 13% for rapid acetylators. These results were published in the May issue of Cancer Epidemiology, Biomarkers & Prevention.
Cooked Meat and Breast Cancer
Kala Visvanathan, M.D., from Johns Hopkins School of Hygiene and Public Health in Baltimore, presented another preliminary finding about the increased breast cancer risk in women who eat flame-broiled foods and have polymorphisms in specific metabolic enzymes.
It is known that the higher cooking temperature of flame-broiled meats (foods cooked in direct heat, such as those grilled over charcoal, wood, or fire) produce higher levels of heterocylic amines and polyaromatic hydrocarbons compared with oven-roasted or baked meats. Both HCAs and PAHs have been shown to be carcinogenic in rodents. In humans, an increased risk of developing colon cancer is associated with high intakes of well-done, fried, or barbequed meats.
However, the association between consumption of meat cooked in direct heat and the development of breast cancer is less clear. Specific metabolic enzymes, glutathione-S-transferases (GSTM1, GSTT1, and GSTP1), are thought to be involved in the detoxification of HCAs and PAHs, whereas NAT2 activates HCAs. Polymorphisms of these enzymes occur in more than 45% of the population. (Current research indicates that NAT2 inactivates some carcinogens, such as aromatic amines found in tobacco smoke, and activates others, such as HCAs found in well-done meat.)
Visvanathans study involved 98 women with breast cancer and 100 controls. "The women who ate flame-broiled food greater than twice a month had almost a twofold increase in the risk of breast cancer compared to those who did not," said Visvanathan. Interestingly, this risk was limited to women who were either rapid acetylators of NAT2 or had absent or decreased GSTM1 and GSTP1 activity. When the genotypes were assessed in combination, the risk of breast cancer in women who ate flame-broiled food increased as the number of high-risk genotypes increased. "You dont see this with people who didnt eat flame-broiled food, even though they have the high-risk genotypes," said Visvanathan.
Immigration Patterns
A third researcher is looking for geneenvironment interactions that might explain the rapid increase in colorectal cancer rates in the 214,000 Japanese who migrated to Hawaii from 1886 to 1924. The colorectal cancer rates for the Japanese in Hawaii and California are now the highest in the world and even surpass the host population.
Based on a lifestyle questionnaire completed by nearly 1,200 Japanese migrants diagnosed with colorectal cancer and 1,192 controls, Loïc Le Marchand, M.D., Ph.D, and his colleagues from the University of Hawaii in Honolulu found that the Japanese consumed more red meat, particularly beef and processed meats, and less fiber and vegetables than Caucasians.
Since the HCAs created in red meat by high-temperature cooking are activated by two carcinogen-metabolizing enzymes, NAT2 and a type of cytochrome P450, CYP1A2, Le Marchand hypothesized that the genotypes of these enzymes may explain the high risk of colorectal cancer in Japanese Americans. The fast acetylator genotype (without the polymorphism) is present in 90% of Japanese compared with 45% of Caucasians; the frequency of the CYP1A2 phenotype is similar in both groups.
Preliminary results published in a 1999 Journal of the National Cancer Institute Monograph titled "Innovative Study Designs and Analytic Approaches to the Genetic Epidemiology of Cancer," suggest that consumption of well-done red meat, combined with a specific genotype of NAT2 and CYP1A2, may increase colorectal cancer risk substantially. Among the Japanese migrants who ate well-done red meat, those without the polymorphisms had a 3.6 times greater risk of developing colon cancer than those with the polymorphisms (see chart above).
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Neil Caporaso, M.D., from NCIs Division of Cancer Epidemiology and Genetics, said that focus of genetic research is moving on from the study of enzymes that either detoxify or activate known carcinogens. "We have branched out from metabolic genes to DNA repair genes, genes involved in hormone metabolism, and genes that may confer resistance to either radiation-induced cancers or viruses that cause cancer," he said.
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"Now there are many studies involving geneenvironmental interactions," said Caporaso. "I would say that in our division virtually every new study of a major cancerall the large studies for breast, colon, lung, kidney, bladder, and prostatehave important genetic components."
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