Strategic Investments in

Molecular Epidemiology

Our GoalUnderstand the behavioral, environmental, genetic, and epigenetic causes of the vast majority of cancers in the human population in order to generate new means of prevention, detection, and treatment.

Cancer is a complex disease that develops when the genes that regulate such functions as cell growth, cell death, and signal response are impaired. This impairment can occur through either genetic or epigenetic pathways. Genetic errors are caused by structural changes in the DNA of a person's genes, whereas epigenetic transformation refers to those processes which cause normal cells to become tumor cells without the occurrence of any mutations affecting DNA or other genetic machinery. Some of these genetic and/or epigenetic errors are inherited. Others result from certain environmental exposures or individual behaviors such as energy balance status; tobacco and alcohol use; exposure to ionizing, solar, and other radiation; viruses and other infectious agents; imbalances in hormones and metabolic processes; and exposure to chemicals in the occupational and general environment. It is important to understand the roles of both inherited susceptibility and lifestyle or environmental risk factors for cancer. Furthermore, we need to uncover the interactions among genetic and environmental risk factors, harnessing the statistical power of bioinformatics and taking advantage of the emerging insights from integrative biology.

NCI is developing novel ways to unravel the complexities of inherited and environmental contributions to cancer. We are supporting individual efforts as well as large collaborative programs to maximize the sharing of population data, biospecimens, laboratory models, and in vitro observations. In particular, large-scale studies with heightened levels of interdisciplinary cooperation and innovation are encouraged. Future 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 or mitigate adverse exposures. This expanded information will enable NCI to develop more effective approaches for the prediction, prevention, early detection, and treatment of cancer in all population groups.

Expanding Our Understanding of Specific Cancers

With increased resources in Fiscal Year 2006, we will expand efforts to understand specific types of cancer through consortia of cohort and case-control studies and consortia of cancer-prone families that integrate genomics, epigenomics, proteomics, and other emerging technologies into epidemiologic studies. We will:

Initiate large-scale studies of highly lethal cancers (e.g., cancers of the pancreas, liver, and esophagus).
Continue to conduct and analyze consortial studies of breast and prostate cancer and non-Hodgkin's lymphoma and initiate consortial studies of ovarian and brain cancers.
Expand existing international consortia for family-based studies (e.g., melanoma, leukemia, lymphoma, and testicular, colon, breast, prostate, and pancreatic cancers) and initiate family-based consortia for other cancers, in order to identify genetic determinants.
Expand the number of participants, population diversity, and types of biospecimens (including tumor specimens) in these consortia.
Develop innovative review and reward processes that foster large-scale consortial research.

Expanding Studies of Behavioral and Environmental Risk Factors

We will also use new resources to expand studies on the influence of behavioral and environmental factors on the risk of cancer induction and progression, utilizing genetic and molecular probes, including studies in populations with exceptional or changing cancer rates or unusual environmental exposures. International studies and investigations of populations in transition, including migrant populations, provide particular opportunities for identifying biomarkers of carcinogenic exposure, genetic susceptibility, precursor states, and mechanisms of cancer causation. Special emphasis will be given to studies of specific behavioral factors (e.g., tobacco and alcohol use, energy balance) and their relation to cancer risk. In Fiscal Year 2006, we will:

Fund and conduct etiologic studies targeted to U.S. minority groups, including Hispanic and African American populations.
Initiate and fund studies of populations in transition, such as populations in Asia and migrant populations in the United States.
Incorporate instruments to collect enhanced behavioral information on dietary and environmental exposures in case-control and cohort studies.
Conduct population-based studies of cancer risk associated with tobacco and other products, including studies that explore molecular damage in former smokers.

Integrating Population Science with Genomics and Other Technologies

We are now in a position to greatly expand the knowledge base of cancer risk factors and biologic mechanisms through the convergence of epidemiologic and molecular approaches and the integration of population science with genomics and other emerging technologies. Research in this area has begun to yield important insights into a fundamental understanding of cancer causation, including the role of environmental and genetic determinants and their interactions. With sufficient resources in Fiscal Year 2006, we will establish a much needed, regional network of high-throughput laboratories for existing and emerging biomarkers of cancer risk. The network will provide the support for the genomic, molecular, and biochemical components of the molecular epidemiology consortia. We will:

Build a network of high-throughput genotyping laboratories that incorporate advances in genomic technology into large-scale population studies.
Initiate programs to implement public health measures and educational activities based on emerging genomic, epigenomic, and proteomic technologies.

Partnering to Leverage Resources

Partnerships with clinical oncology groups will allow us to leverage research resources and integrate clinical, laboratory, and population sciences. We will:

Expand the program of surveillance and research into second primary cancers and recurrence to determine risk factors, such as the role of therapy and genetic susceptibility mechanisms, including DNA repair.
Conduct collaborative studies of etiology and natural history with the Gynecologic Oncology and Children's Oncology Groups conducting clinical trials.
Provide supplemental funds to Cancer Centers to develop molecular epidemiology capabilities, especially for hospital-based case-control studies of highly lethal cancers.
Develop population studies to identify genetic factors that affect tumor progression, prognosis, therapeutic outcomes, and side effects (e.g., pharmacogenomics).

Stimulating Cross Training and Interdisciplinary Research

Finally, initiatives to stimulate cross training and interdisciplinary and multidisciplinary research opportunities will provide a pool of investigators poised to advance the new and integrated objectives in molecular epidemiology. We will use new resources to:

Work with medical and public health schools to develop joint training programs and new curricula in genetic and molecular epidemiology.
Initiate new training awards for predoctoral students in interdisciplinary and multidisciplinary research relevant to molecular epidemiology.
Initiate new interdisciplinary and multidisciplinary research awards in molecular epidemiology.

Molecular Epidemiology Budget Increase Request for Fiscal Year 2006
Expanding understanding of specific cancers Large-scale studies of highly lethal cancers Disease-specific consortial studies International consortia for family studies Expansion of and incentives for consortial research	$35.25 M
Expanding studies of risk factors U.S. minority groups Populations in transition Lifestyle & environmental exposures	9.50 M
Integrating population science with emerging technologies Network of high-throughput genotyping laboratories Public health & education programs	6.00 M
Partnering to leverage research resources Research on second primary cancers & recurrence Collaborative studies with the Gynecologic & Children's Oncology Groups Supplemental funds to Cancer Centers	7.50 M
Stimulating training & interdisciplinary research Joint training programs with medical & public health schools Interdisciplinary training & research awards	1.40 M
Management & Support	1.02 M
Total	$60.67 M

Strategic Partnerships Advance Studies in Molecular Epidemiology

Epidemiology has been depicted as a scientific approach that moves slowly but with great force. By incorporating powerful new tools generated by recent advances in genomics and molecular sciences, however, we have an unparalleled opportunity to move more quickly and with greater impact than ever before. Poised to accelerate knowledge about the genetic and environmental components of cancer initiation and progression, our investments in Molecular Epidemiology will help identify new preventive, diagnostic, and therapeutic interventions.

Cultivating strategic partnerships that link epidemiologists with one another and with genomicists and other investigators from the clinical, basic, and population sciences is integral to these investments. This transdisciplinary team-based approach responds to a growing consensus in the scientific community that the full potential of genomic and other emerging technologies will require large-scale epidemiologic studies. Study designs must have the efficiency and power to identify, from questionnaires and biospecimen collections, common low-penetrant susceptibility genes and their interactions with exogenous or endogenous exposures. This can be accomplished through consortia that combine the resources of several cohort and/or case-control studies in a coordinated approach that enables rapid replication of positive findings using independent datasets. This strategy avoids the cumbersome and expensive trial-and-error process that often occurs when false-positive findings from individual studies appear in the literature. When reproducible findings emerge in the consortia, pooling of datasets provides the statistical power to quantify the risks associated with specific gene variants and exposures and to enable subset analyses that uncover gene-gene and gene-environment interactions.

One such partnership is the Consortium of Cohorts, an international collaboration of investigators responsible for 23 independently funded population cohorts involving 1.2 million individuals. Each cohort will characterize thousands of individuals who have developed cancer with extensive information on known or suspected risk factors and biospecimens (including germline DNA) collected prior to diagnosis. This consortium provides an integrative framework for nested case-control studies of specific cancers arising within the cohorts and opportunities to systematically evaluate molecular and biochemical biomarkers of susceptibility and early-stage disease.

Other types of strategic partnerships are under development, including international case-control consortia of investigators responsible for population- or hospital-based studies of less common cancers that cannot be easily evaluated in cohort studies. In addition, several scientists interested in familial cancer have formed international family-based consortia. Current emphasis is on familial syndromes in which high penetrant genes have eluded discovery and on opportunities to identify genetic and environmental modifiers of inherited risk.

Many complex scientific, administrative, and cultural challenges are involved in developing these team-based transdisciplinary partnerships, which seemingly run counter to the traditional model of individual investigators or groups that work independently. The two strategies are really complementary and synergistic, however, and they are speeding the discovery of causal agents and pathways, early detection markers, and interventions designed to prevent and control cancer.

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