Genes and the Environment

Goal

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

Introduction

Cancer is a complex disease that develops when errors occur in a person's genes. Some of these genetic errors are inherited. Others result from certain environmental exposures or individual behaviors, usually coupled with inherited susceptibility.

Through the use of increasingly sophisticated molecular technologies and the tremendous resource generated by the mapping of the human genome, scientists now know that some inherited genetic errors nearly always give rise to cancer, regardless of a patient's environmental or lifestyle history. For example, carriers of mutations in the gene for Familial Adenomatous Polyposis are almost certain to develop colon cancer.

Other mutations present at birth only lead to cancer in combination with certain environmental exposures. This relationship is seen in women with BRACA mutations, who are at increased risk for hormonally induced breast cancers.

Still other cancers are caused by long-term damage to multiple genes caused by environmental factors, with some people inherently at higher risk than others. For instance, people with certain combinations of genetic mutations to the NAT2 gene are at increased risk for smoking-related bladder cancer.

New tools and technologies are helping us to better assess who is at risk for specific cancers based on genetic makeup and environmental exposures:

• Scientists have developed technologies to compare complex profiles of genes and proteins from cancer patients to corresponding profiles of cancer-free individuals. This innovation is helping to identify specific molecular profiles associated with cancer risk.
• We are increasingly able to identify and assess a variety of carcinogenic exposures encountered outdoors, in the home, and in the workplace. These include pollutants in air, water, and soil; components of food, tobacco, alcohol, and drugs; sunlight and other forms of radiation; and infectious agents.
• Other new technologies are revealing the intricate biological processes involved in the development of cancer.

To build on this progress, NCI must:

• Continue to develop novel ways to study the complexities of genetic and environmental contributions to cancer.
• Support both individual efforts and large collaborative programs to maximize the availability of population data, biospecimens, laboratory models, and in vitro observations. In particular, large-scale studies with new levels of interdisciplinary cooperation and innovation are needed.

These investments will help scientists uncover environmental risk factors, identify genetically susceptible individuals, develop appropriate interventions and precautions for people at high risk, and generate new individual and public health strategies to avoid adverse exposures.

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Progress in Pursuit of Our Goal

• Building Capacity through Large-Scale Collaborations
• Assessing and Measuring Environmental Exposures
• Discovering and Characterizing Cancer Predisposing Genes in High-Risk Families
• Developing and Improving Resources for Gene Discovery and Characterization
• Improving Quality Control Measures to Maximize the Value of Specimens

• Supporting Intervention Trials and Translational Research on Inherited Susceptibility

Discovery

Building Capacity through Large-Scale Collaborations

NCI continues to promote collaboration through cohort consortia, bringing together researchers across the United States and Europe who are studying the same disease site to collaborate and pool exposure data and biospecimens. The Cohort Consortium for Breast and Prostate Cancer pioneered the approach and developed the Hormone-Related Gene Variants program to:

• Identify genes that may influence a person's susceptibility to hormone-related breast or prostate cancer.
• Develop methods of data sharing across genome and genotyping centers, removing a major obstacle to consortium research.

Future plans call for establishing similar data pooling for cohort studies of less common cancers where analyses of this type would otherwise be impossible.

NCI also supports development of case-control consortia composed of epidemiologic investigators studying less common cancers. For example:

• The InterLymph Consortium is studying the genetic and environmental basis of non-Hodgkin's lymphoma.
• Another consortium is focusing on brain tumors.
• Members of the NCI-supported Health Maintenance Organization Cancer Research Network are pooling their resources to develop the largest ever case-control study of pancreatic cancer.
• We are examining the feasibility of a cohort study in India to focus on nutrition and gene-diet interactions in cancer causation.

Assessing and Measuring Environmental Exposures

NCI and the National Institute of Environmental Health Sciences (NIEHS) continue to support interdisciplinary collaborations for improving research tools used in etiologic studies of cancer and risk assessment. For example, these institutes are funding centers for the study of breast cancer risk associated with environmental exposures and several projects to support the use of geographic information systems in cancer epidemiology and control studies. NCI and NIEHS collaborations encourage the development and use of innovative methods for assessing difficult-to-measure environmental exposures.

NCI scientists are using innovative nanotechnologies in molecular profiling to examine chromosomal alterations and changes in protein levels following exposure to environmental carcinogens. For example, scientists have found that changes in the levels of proteins with genes altered by the biochemical process of methylation are associated with the development of cancer.

Discovering and Characterizing Cancer Predisposing Genes in High-Risk Families

NCI's Interdisciplinary Studies in the Genetic Epidemiology of Cancer emphasize case-control and familial studies of gene-environment interactions for various forms of cancer. NCI-supported work includes:

• A consortium of investigators searching for pancreatic cancer susceptibility genes.
• The Colon, Breast, and Ovarian Cancer Family Registries (CFRs), a high-risk families tissue resource.
• Other family registries and collaborative groups working to identify susceptibility genes for prostate cancer and other familial cancer syndromes including melanoma, renal cancer, testicular cancer, and brain tumors.

The Cancer Genetics Network (CGN) is a major NCI-supported infrastructure for studies of persons at high risk for developing cancer and for related translational research. CGN pilot studies combine existing and prospectively collected data to discover potentially important gene-environment interactions. The Network 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. The CGN implemented and improved upon a state-of-the-art clinical trials informatics system (Trial-DB) across all Network sites.

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Developing and Improving Resources for Gene Discovery and Characterization

NCI is providing readily available resources to support researchers studying gene-environment interactions in cancer causation, incuding the following:

• The Cancer Genome Anatomy Project (CGAP) continues to provide genomic resources for identifying and studying cancer genes. For example, CGAP's Mammalian Gene Collection establishes reference clones validated by sequence analysis for research use and has importance for both in vitro and population-based studies. The SNP500 program provides sequence verification of single nucleotide polymorphisms (SNPs). SNP500 will also develop assays for the Cohort Consortium, making all information immediately available on the Web. (Click here for more information on these and other CGAP programs.)

• NCI has developed a high-throughput Core Genotyping Facility (CGF) to support case-control and cohort studies in partnerships with the National Human Genome Research Institute, the Centers for Disease Control and Prevention, and academic and commercial organizations. The CGF provides high-throughput genotyping and gene sequencing, including verification of SNPs and other types of genetic variations. CGF researchers develop and validate assays for gene sequence verification in conjunction with the SNP500 cancer program. The Facility is also a test site for the development of policies, systems, and infrastructure to expedite data analysis of large-scale interdisciplinary studies and to enhance data sharing.

• CGN has substantially increased the number of participating patients and family members in its biospecimen repository.

• CFRs are developing a repository of EBV-transformed cell lines from patients and selected family members for use by researchers.

• The Gail Model is a statistical tool to help estimate a woman's risk of breast cancer based on a number of predisposing factors, including family history. A study examining mammographic density as a risk factor for breast cancer development was completed recently, showing this characteristic reliable enough to be formally included in the model.

• NCI continues to support workshops to develop collaborative studies between population scientists and groups developing mouse models of cancer and on the localization and characterization of cancer susceptibility genes.

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Improving Quality Control Measures to Maximize the Value of Specimens

Biological specimens collected from patients, people at risk for cancer, and their families must be processed and stored according to strict requirements. This level of care is needed to ensure that the specimens are of sufficient quality to be used in a wide variety of assays and test procedures. NCI and partners are helping to develop and disseminate procedures to safeguard the quality of biological samples. For example:

• CFRs support academic-commercial biotechnology partnerships to establish an integrated and standardized infrastructure for the collection and management of biospecimens from large populations, the production of related microarrays, and the development of novel relational data management software for associated molecular, clinical, and risk factor data.
• CGF activities include sponsorship of conferences on specimen handling and quality control for DNA storage and analysis.
• NCI's intramural Epidemiology and Carcinogenesis Faculty has sponsored national workshops on how to process specimens to optimize their use in conjunction with current technologies. This faculty also helped found the International Society for Biological and Environmental Repositories, which developed a "best practices" document for the collection and storage of specimens.
• A series of NCI-supported studies have established an optimal protocol for collecting oral epithelial cell samples for genetic testing from large populations by mail, and pilot work has established acceptably high rates of compliance by study populations. Progress has been made in addressing issues of potential DNA damage by irradiation of samples during transport through the mail.
• The NCI Center for Bioinformatics has recommended a set of informatics standards, guidelines, and procedures for handling and storage of biospecimens.

Development

Supporting Intervention Trials and Translational Research on Inherited Susceptibility

NCI scientists and CGN are conducting a collaborative, prospective study of risk reduction in women at high genetic risk for breast and ovarian cancers. Researchers are comparing and evaluating two risk-reduction strategies: preventive removal of the ovaries and fallopian tubes and a novel screening strategy. Investigators will include the impact of these procedures on quality of life in their evaluation.

NCI is also collaborating with the National Surgical Adjuvant Breast and Bowel Project to genotype participants in the Breast Cancer Prevention Trial, which showed that tamoxifen reduced the risk of breast cancer among high-risk women. Collaborators will focus on determining if variants in genes related to estrogen and tamoxifen metabolism can identify subsets of women who might be more or less likely to benefit from tamoxifen.

NCI is researching alternative screening techniques for early breast cancer detection in women genetically at risk for the disease. These include magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, and in vitro analysis of cells obtained from breast duct lavage.

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Objectives and Fiscal Year 2005 Milestones and Required Funding Increases

Discovery

Development

Discovery

Development

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