Advancing Discovery and Its Application

Genes and the Environment

The Opportunity

The debate over nature vs. nurture is as old as scientific inquiry itself. Is it a particular characteristic passed from one generation to another, or is it imposed by the world into which the individual is born? Especially with respect to cancer, that question has become far more difficult, because we now know that elements in the environment or a person's lifestyle can damage genes, and we are finding that some genes seem to require certain conditions to give rise to cancer, while others virtually guarantee its occurrence. We have been able to:

• Identify some of the human genes that make people susceptible to cancer,
• Apply increasingly sophisticated molecular technologies to analyze genetic changes, and
• Examine the relationship between disease development and individual genetic profiles.

We have learned about a variety of carcinogenic environmental factors including:

• Pollutants in air, water, and soil;
• Components of food, tobacco, alcohol, and drugs;
• Sunlight and other forms of radiation; and
• Infectious agents.

Early efforts to discover how genes and environmental factors interact to cause cancer are showing promise but also highlight the complexity of the puzzle. Some genes have proven to be so powerful that their presence in an individual makes cancer highly predictable. For example, carriers of the gene for Familial Adenomatous Polyposis are almost certain to develop colon cancer. But an inherited predisposition to other types of cancer requires additional factors for cancer to occur, such as the presence of other genes or exposures to chemicals in the environment. Mutations in the susceptibility genes BRCA1 and BRCA2 are risk factors for breast cancer that may arise from a combination of factors. Similarly, some environmental exposures, such as tobacco use, can be strong, but not certain, predictors of cancer.

We want to learn how certain environmental exposures increase the cancer risk for genetically susceptible subgroups and uncover elements of the gene-environment interaction that can lead to tangible improvements in our ability to prevent, detect, and control cancer. Once we can define the cancer risks associated with specific environmental and genetic factors and their interactions, we can then develop new individual and public health strategies to avoid adverse exposures, check genetic susceptibility earlier, and identify appropriate interventions and precautions for people at high risk.

To make progress in this area, NCI needs to develop new ways to study cancer susceptibility genes, environmental exposures, and their interactions and to maximize the availability and use of large amounts of population data, biospecimens, laboratory models, and other resources. Large-scale studies with new levels of interdisciplinary cooperation and innovation from the cancer community will be needed to achieve tangible improvements in clinical practice and public health. The Cohort Consortium is the centerpiece of studies on genes, the environment, and cancer. Through this program, we are breaking new ground in how to conduct these large population studies and bringing epidemiologists, genomicists, and other investigators together for collaborative research.

Top of Page

Progress in Pursuit of Our Goal

Building Capacity through Large-Scale Collaborations

NCI is continuing to build the Cohort Consortium to address the need for large-scale collaborations in genetic epidemiology to unlock the full potential of new discoveries in genomics. This consortium is comprised of well established investigators who, individually, had initiated over 15 separate prospective studies of large population groups. Working together, the Consortium will pool high quality environmental exposure data along with information from biologic specimens suitable for genetic analysis from over 700,000 participants. One group within the Consortium has developed a truly novel four-year collaborative study to identify critical gene-environment interactions in endogenous hormone pathways for over 7,000 cases each of breast and prostate cancer. A second group is pooling data for less common cancers, such as pancreatic cancers.

The Case-Control Consortium is also investigating genetic and environmental determinants of cancer. For non-Hodgkin's lymphoma, several investigators who have completed individual studies and collected biologic specimens, are formulating a combined study to give them the statistical power to uncover key gene-environment interactions. A second group, of investigators, members of the NCI-supported (http://healthservices.cancer.gov/hmo/ ) HMO Cancer Research Network, is pooling its resources to develop the largest case-control study to date of pancreatic cancer. These researchers will employ "real time" electronic reporting of pathology, laboratory, radiology, and outpatient physician visit findings, resulting in the identification of pancreatic cancer within ten working days of diagnosis. The purpose of this study is to develop a better understanding of risk factors for sporadic and familial pancreatic cancer and ultimately to use this knowledge for earlier detection and prevention.

Assessing and Measuring Environmental Exposures

Few population studies have investigated the question of whether environmental endocrine disruptors have a role in adverse health effects, including cancer in humans. NCI is collaborating with the National Institute for Occupational Safety and Health, the Environmental Protection Agency, and the National Institute of Environmental Health Sciences to study organochlorine pesticides and polychlorinated biphenyls (PCBs) and their possible association with testicular and breast cancer risk. Researchers are following groups of infants born to mothers exposed to very high versus low (background) levels of PCBs through childhood and adolescence. The study provides a unique mechanism to assess whether early life exposures are critical in the eventual occurrence of cancer.

NCI is funding 12 grants for geographic based research in cancer control and epidemiology. Half of these projects will apply innovative methods for assessing difficult to measure environmental exposures. One such innovation will use satellite imagery to estimate potential exposure to agricultural pesticides. The other grants will be used to develop methods and software to detect geographic patterns and clusters of cancer rates and to explore associations with environmental, sociodemographic, and access to care factors.

The recently completed Observing Protein and Energy Nutrition Study assessed the measurement error inherent to studies in which patients must complete questionnaires or surveys to report their dietary intake. Investigators in this study, the largest ever of its kind, are comparing self-reported dietary intake data from 484 men and women with biomarkers that will reflect the actual diet of the patient. The results of the study will give us a better grasp of the reporting error so that we can more accurately interpret the findings of self-report dietary studies.

Molecular profiling using innovative micro-technologies may be used to examine changes in chromosome alterations and protein levels following exposures to various environmental toxins that correlate with the appearance of cancer. For example:

• Scientists have found that changes in the levels of particular proteins (those whose genes may be altered by the biochemical process of methylation) have been associated with the development of cancer. NCI-funded molecular micro-technology research may permit identification of new environmental exposures that change the number of these important proteins in tissues.
• Chromosome alterations in cancers are common and complex and often difficult to assess. New molecular technologies may be used to rapidly identify changes in chromosomes after exposure to environmental chemicals.

Discovering and Characterizing Cancer Predisposing Genes

The Breast, Ovarian and Colorectal Cancer Family Registries will expand:

1. The epidemiologic and clinical follow-up of current participating high-risk families;
2. The molecular characterization of known colorectal, breast, and ovarian cancer susceptibility genes; and
3. The exploration of DNA methylation and non-methylation related mismatch repair mechanisms and their relationship to cancer susceptibility.

Studies will continue in breast, ovarian, and colon cancer to search for new susceptibility or modifier genes; better understand the interactions of genetic markers with dietary and hormonal factors; and develop new models for cancer risk prediction.

Family registries and collaborative groups are identifying susceptibility genes for prostate cancer as well as other familial cancer syndromes and discovering mutations of known genes for cancer site specific susceptibility. NCI is also supporting new groups of investigators to use large registries of cancer prone families. For example, a large international genetic epidemiology consortium is studying melanoma.

Developing Tools for Gene Discovery and Characterization

NCI is developing the high throughput Core Genotyping Facility (CGF) capable of performing 40,000 genotypes every six weeks. The work will expand to 100,000 genotypes with the installation of an advanced Laboratory Information Management System. The CGF program has established partnerships with the National Human Genome Research Institute and several academic and commercial centers and is providing genomics support for the first Cohort Consortium study, described above.

The Centers for Disease Control and Prevention are funding three Genomics and Public Health Centers to develop methodologic standards specific to the collection and reporting of data from NCI-based population genetics research. This interagency collaboration is designed to more effectively move research results into clinical practice and public health.

The Gail Model, developed at NCI, is a statistical tool to help estimate a woman's risk of breast cancer based on a number of predisposing factors. A study of the reliability of mammographic densities was completed recently, and this characteristic has been found to be reliable enough to be formally included in the model.

Supporting Intervention Trials and Translational Research on Inherited Susceptibility

The Cancer Genetics Network (CGN) is a major NCI-supported infrastructure for studies of persons at high risk of cancer and for related translational research. CGN pilot studies combine existing and prospectively collected data to discover potentially important gene-environment interactions. The network collectively holds epidemiologic data on participants consistent with data collected by other NCI-supported consortia and registries allowing the information to be used either independently or in combination with other groups to explore gene-environment interactions.

The Plan - Genes and the Environment

Discover genetic, environmental, and lifestyle factors and their interactions that define cancer risk and that can inform the development of new strategies for prevention, early detection, and treatment.

Objectives, Milestones, and Funding Increases Required for Fiscal Year 2004

Top of Page

Top of Page

Top of Page

Top of Page

Top of Page

Top of Page

Behavioral Factors and the Risk of Cancer

A number of studies have examined the relationship between cancer and a range of behavioral or lifestyle factors such as tobacco use, diet, physical activity, and alcohol consumption. Some researchers estimate that as many as 50 to 75 percent of cancer deaths in the United States are caused by behaviors or conditions that can be altered.

• Cigarette smoking is the most preventable cause of death in the United States. It leads to nearly one-third of the nation's cancer deaths and is the major cause of lung cancer incidence and mortality. Tobacco use can also cause cancers of the larynx, mouth, esophagus, pharynx, and bladder, and it plays a role in cancers of the pancreas, kidney, and cervix.
• Obesity increases the risk for several cancers including colon cancer, post-menopausal breast cancer, endometrial cancer, gastric cardia, and adenocarcinoma of the esophagus. People whose diets are rich in fruits and vegetables have a lower risk of getting cancers of the lung, mouth, pharynx, stomach, and colon.
• Sedentary lifestyle is a risk factor for colon and breast cancer, and physical activity has been linked to decreased incidence of cancer, including a 50 percent lower risk of getting colon cancer as well as to improved quality of life and recovery for cancer patients.
• High alcohol intake increases the risk of cancers of the mouth, esophagus, pharynx, larynx, and liver in men and women, and breast cancer in women.

Choosing healthy behaviors such as not smoking, maintaining a healthy weight, being physically active, eating a low-fat diet rich in fruits and vegetables, and avoiding too much alcohol can help to reduce cancer risk.

Endocrine disruptors are synthetic or naturally occurring chemicals that affect the balance of hormonal functions. Back.

An exogenous exposure originates from outside the body. An endogenous exposure originates from within the body. Back.