Genes and the Environment
Goal
The Opportunity
Progress in Pursuit of Our Goal
2003 Plan and Budget Increase Request
Goal
Discover genetic, environmental, and lifestyle factors and their interactions that define cancer risk and inform strategies for cancer control.
The Opportunity
As we better understand the interplay between inherited susceptibility to cancer and environmental risk factors, we will be able to develop more meaningful approaches to cancer prevention, early detection, and treatment.
Until recently, we have pursued separate lines of inquiry for cancer genetics and environmental risk factors for cancer. As such, 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.
- Examine the relationship between disease development and individual genetic profiles.
We have learned about a variety of carcinogenic environmental factors not only in the outdoors but also in the home and workplace. These include:
- Pollutants in air, water, and soil
- Components of food, tobacco, alcohol, and drugs
- Sunlight and other forms of radiation
- 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 other factors for cancer to occur, such as the presence of other genes or exposures to chemicals in the environment. For example, mutations in the susceptibility genes BRCA1 and BRCA2 are risk factors for breast cancer that may be related to a combination of factors. Similarly, some environmental exposures - tobacco use, for example - can be strong, but not certain, predictors of cancer.
NCI's opportunity is to uncover elements of the gene-environment interaction that can lead to tangible improvements in our ability to prevent and control cancer. For example, we expect to:
- Identify previously unsuspected carcinogens through the study of newly discovered genes that predispose people to cancer.
- Learn how certain environmental exposures increase the cancer risk for genetically susceptible subgroups.
When we can define the cancer risks associated with specific environmental and genetic factors and their interactions, we can:
- Develop new individual and public health strategies to avoid adverse exposures.
- Check genetic susceptibility earlier.
- Identify appropriate treatment regimes.
- Take special precautions for people at high-risk.
To progress in this area and achieve tangible improvements in medical practice and public health, NCI needs to:
- Develop new ways to study cancer genetics, environmental exposures, and their interaction.
- Maximize the availability and use of large amounts of research data and other resources.
- Conduct large-scale studies through new levels of cooperation and innovation from the cancer community.
Progress in Pursuit of Our Goal
NCI is pursuing research opportunities in five growth areas to better understand cancer-related genes, environmental factors, and their interaction.
Building the capacity to understand genetic variation, identify important biologic exposures, and explore the complex gene-environment interaction
Examining a broad spectrum of approaches to assess and measure environmental exposures
Advancing research to discover and characterize cancer pre-disposing genes
Supporting the development of tools for use in gene discovery and characterization
Establishing a productive infrastructure to support intervention trials on inherited susceptibility to cancer
We are building the capacity to understand genetic variation, identify important biologic exposures, and explore the complex interaction among them through research collaborations with many partners.
- Investigators already involved in 15 separate prospective studies of large population groups are pooling high quality environmental exposure data along with tissue, blood, and other body fluid samples suitable for genetic analysis to form a combined study size of 700,000 participants, large enough to yield significant findings.
Some members of this Cohort Consortium of investigators are involved in a collaboration to uncover gene-environment interactions by compiling and examining more than 7,000 cases each of breast and prostate cancer.
- Two other groups of investigators are using the case-control approach to identify genetic and environmental determinants of non-Hodgkin's lymphoma (NHL) and brain cancer. These Case-Control Consortia of investigators are pooling data from more than 5,000 patients with NHL and more than 3,000 with brain tumors.
- Two groups of researchers are partnering to collect high quality cancer registry data on environmental exposures of patients and a variety of biologic specimens from these patients for use in genetic analysis. These data and analyses will be compared with those of non-cancer patients, and the resulting information will serve as a resource for the research community in its search for susceptibility genes and environmental carcinogens.
Examining a broad spectrum of approaches to assess and measure environmental exposures.
- Non-invasive methods for detecting cancers, carcinogenic exposures, and genetic susceptibility can ease the stress on patients and make screening for environmental exposures and early signs of cancer more thorough and affordable. These methods also are well suited to use in large-scale research studies. Researchers are examining options that would allow:
- Screening for lung cancer using a molecular marker in sputum samples.
- Sampling DNA from cheek cells.
- Using saliva samples instead of blood to test for body nutrient levels, hormones, and environmental chemicals.
- Use urine samples to validate patient responses to questions about dietary habits.
- New and easier methods, such as biodosimetry and direct versus surrogate measures, may provide improved ways of assessing difficult-to-measure environmental exposures.
- Collaborative studies with the National Institute for Occupational Safety and Health are improving assessment measures for studying cancer resulting from exposure to low-dose radiation and agricultural pesticides. Sophisticated monitors designed for workers in specific occupations can be used in large groups of workers.
- Techniques using geographic information systems to support the Long Island Breast Cancer Study of complex toxicological and environmental exposures and breast cancer incidence can be applied to other areas of research as well.
Advancing research to discover and characterize cancer predisposing genes by building on NCI-supported cancer family registries and promoting collaborations among investigators who have studied large numbers of families with cancer.
- The Cancer Family Registry (CFR), a large international registry of more than 8,500 ethnically diverse families and 21,000 participants, focuses on highly penetrant breast and ovarian cancer genes by:
- Recording information on cancer family history, demographics, environmental and lifestyle risk factors.
- Recording clinical data.
- Maintaining a bank of biological specimens.
The CFR is supporting several studies to provide the information needed to make prevention and treatment decisions. One such study examines the effects of hormones as well as diet, body size, physical activity, alcohol consumption, and radiation on breast cancer risk among carriers of BRCA1 and BRCA2 mutations.
- A second large resource, the Colon Cancer Family Registry, has assembled data on more than 5,000 families, including more than 150 families with hereditary non-polyposis colon cancer and more than 300 with two or more first-degree relatives who have the cancer.
- Other groups of investigators are working to discover and characterize highly penetrant familial genes associated with melanoma, ataxia telangiectasia, and prostate and lung cancers.
Supporting the development of a number of tools for use in gene discovery and characterization. These efforts are needed to advance our understanding of gene-environment interactions and the application of that knowledge.
- Through the Mouse Models of Human Cancers Consortium (MMHCC), scientists are:
- Capitalizing on the remarkable correspondence between the human and mouse genomes to identify human cancer-related genes.
- Facilitating rapid cancer gene discovery by adding mouse models of known familial cancer susceptibility genes.
In collaboration with population scientists studying cancer families, MMHCC researchers applied a new timesaving strategy of mouse cross-breeding to quickly pinpoint the BRCA1 breast cancer susceptibility gene. The mouse studies soon revealed the function of the gene and enabled scientists to verify its role in altering susceptibility to breast cancer.
Furthermore, a model for the gene PTEN/MMAC1 may shed light on several types of cancer, including Cowden disease, a syndrome that predisposes family members to breast, brain, prostate, endometrial, and bladder cancers.
- NCI used a risk assessment model that combines several known risk factors in the Tamoxifen Breast Cancer Prevention Trial. The success of the model exemplifies how we can substantially increase our ability to predict breast cancer risk. Scientists have greatly expanded information on risk factors among African American women and are incorporating data from the Women's Health Initiative Trial. Using this Gail Model as a pattern, researchers are now constructing models for both ovarian cancer and colorectal malignancies built on pooled data from large multi-center studies.
- Through the efforts of the Genetic Annotation Initiative (GAI), the genetic information generated by the Cancer Genome Anatomy Project (CGAP) is being made available for research use. More than 30,000 gene-based polymorphisms - DNA variations among individuals - have been identified, and GAI scientists have established high-throughput laboratory assays to detect more than 7,000 of these variants.
As with all of the CGAP resources, materials are available free of charge through the World Wide Web. Scientists can use these tools to investigate the roles of these genes in families and populations.
Establishing a productive infrastructure to support intervention trials on inherited susceptibility to cancer.
Such trials are vitally important to improving our ability to detect and treat cancer earlier. Through the Cancer Genetics Network (CGN), researchers are conducting a number of these studies.
- A pilot study of an early detection technique for ovarian cancer screening in genetically susceptible women involves a CGN partnership with several NCI-supported programs, including the Gynecologic Oncology Clinical Trials Group.
- In another study, researchers are comparing the effectiveness of several existing biostatistical models for estimating breast cancer risk.
- Another group is developing innovative analytical methods to identify colon cancer genes that are as yet undiscovered.
- A pilot study will improve methods for recruiting and retraining individuals and families at high-risk of cancer into clinical trials.
- Finally, a pilot collaborative is coordinating a multi-institutional study of genetic and environmental modifiers of cancer risk in women with BRCA1 and BRCA2 mutations.
To apply the latest findings in human epidemiologic and clinical investigations, the CGN is promoting active collaboration with the Mouse Models of Human Cancers Consortium, the Genetic Annotation Initiative, and the Cancer Genome Anatomy Project.
In addition, CGN is collaborating with the NCI Special Populations Networks for Cancer Awareness Research and Training to ensure wider opportunities for people from diverse communities, including investigators representing those communities, to participate in research on genetic susceptibility to cancer.
Environmental Exposures and Inherited Susceptibility in Cancer
Scientific studies point to three main categories of environmental exposures that contribute to the development of cancer - chemicals, radiation, and viruses or bacteria. Some common examples are:
Chemicals
- Chemicals in the diet
- Home or workplace exposures
- Drugs
- Pollutants in the air, water, or soil
Radiation
- Low strength radiation such as ultraviolet radiation from sunlight
- High strength radiation as from x-rays or radioisotopes
Viruses and bacteria
- Epstein-Barr virus - Burkitt's lymphoma
- Human papillomavirus - cervical cancer
- Hepatitis B virus - liver cancer
- Human T-cell lymphotropic virus - adult T-cell leukemia
- Kaposi's sarcoma associated herpes virus - Kaposi's sarcoma
- H. pylori bacteria - associated with stomach cancer
A person's chances of developing cancer also can be influenced by the inheritance of certain kinds of genetic alterations. For example, specific inherited mutations increase a person's risk of developing some cancers including breast, colon, kidney, bone, and skin. As we better understand the interplay between inherited susceptibility to cancer and environmental risk factors, we can develop more meaningful approaches to cancer care.
The Plan - Genes and the Environment
Goal
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.
Fiscal Year 2003 Objectives, Milestones, and Funding Increases Needed
Top of Page
| Objective 1: Identify new environmental risk factors and susceptibility genes and determine their interactions in cancer causation. |
- Utilize the unique advantages of the Cohort Consortium to investigate exposures best studied in large populations and their interactions with susceptibility genes.
|
|
- Continue the five-center gene-environment risk factor discovery study of breast and prostate cancers while adding studies of other common cancer sites.
|
$3.00 M |
- Expand the number of participants, population diversity, and types of biospecimens.
|
$2.00 M |
- Support Case-Control Consortium investigators to address specific gene-environment interactions in detail. Establish formal resources for discovery efforts by initiating large population-based and hospital-based studies to develop comprehensive data and specimen resources by cancer site. Encourage use of the NCI Atlas of Cancer Mortality and other public use data systems (e.g. Long Island Breast Cancer Study) as a source of study from high-risk areas.
|
$4.00 M |
- Continue improving infrastructure to meet the needs of large, collaborative human population studies.
|
|
- Maximize the utility of specimen resources for human population studies with improved efficiency and cost-effectiveness of specimen collection, processing, storage techniques, and high-throughput assays.
|
$2.00 M |
- Continue developing informatics systems to capture, store, analyze and integrate the massive amount of information generated by these studies.
|
$3.00 M |
- Facilitate the use of new genomic technologies by funding supplements to existing gene-environment focused studies.
|
$2.00 M |
| TOTAL |
$16.0 M |
Top of Page
| Objective 2: Develop new ways to assess and measure environmental exposures for use in population studies. |
- Support development of new methods for characterization of internal dose resulting from complex lifetime exposures.
|
$2.00 M |
- Continue expanding NCI's Innovative Molecular Analysis Technologies Program to develop new, non-invasive techniques for collecting and measuring DNA and proteins in very small amounts of biologic material.
|
$2.00 M |
- Continue support for applying and validating measures of the cumulative cellular, genetic, and molecular effects of environmental exposure through funding supplements for ongoing research programs.
|
$2.00 M |
| TOTAL |
$6.00 M |
Top of Page
| Objective 3: Identify cancer-predisposing genes in high-risk families and investigate how other genes and environmental factors modify expression of these genes. |
- Fund two new consortia of investigators to identify unknown cancer susceptibility genes (e.g., pancreatic cancer).
|
$4.00 M |
- Support interdisciplinary studies for gene discovery and characterization for additional cancer sites by new collaborative family registry groups.
|
$2.00 M |
- Support collection of fresh-frozen tumor tissue and other biospecimens from genetically cancer-prone families for microarray-based molecular signature analyses in NCI-supported large population research resources such as a Cancer Family Registry Web site.
|
$2.00 M |
| TOTAL |
$8.0 M |
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| Objective 4: Develop tools for the study of gene and environment interactions in human populations. |
|
|
- Augment the Mouse Models of Human Cancers Consortium to more rapidly localize interesting genetic regions, increase the number of models for human hereditary cancer genes, decipher environmental factors that modify cancer development, and test biomarkers for early detection.
|
$2.50 M |
- Provide the framework for productive use of genetically engineered mouse models to study human cancer genetics by integrating the study of mouse and human molecular genetics and by cataloging mouse single nucleotide polymorphisms to facilitate genotyping of commonly used mouse strains.
|
$2.50 M |
| TOTAL |
$5.0 M |
Top of Page
| Objective 5: Support collaborative studies of high-risk individuals to address the clinical, behavioral, and societal issues associated with cancer susceptibility. |
- Sustain the Cancer Genetics Network (CGN) as a resource for studies of clinical care for early detection, diagnosis, and treatment of genetically high-risk individuals, including those from minority and underserved populations.
|
$10.00 M |
- Expand support for studies in cancer genetics that examine psychosocial responses to cancer risk communication within average and high-risk populations in order to inform the development of effective educational strategies and resources for patients, providers, and the public.
|
$4.00 M |
- Continue to support research in cancer survivorship to evaluate physiologic and/or psychosocial effects of cancer or its treatment among survivors of cancer, and examine the role of genetic factors in these sequelae.
|
$2.00 M |
- Refine cancer risk prediction methods/models to integrate genetic and environmental determinants of cancer by developing methods to estimate individual risk. Merge models that are primarily genetic based with those that are primarily environmental. Refine models that predict cancer risk and other outcomes among diverse populations to estimate population burden and policy implications.
|
$1.00 M |
- Collaborate with the Centers for Disease Control and Prevention's Genomics and Public Health Centers to develop methodological standards specific to the collection and reporting of data from NCI consortia on gene-environment interactions, effectively relating these results to medical practice and public health.
|
$0.50M |
| TOTAL |
$17.5 M |