Molecular Epidemiology: A Time for Strategic Partnerships
Epidemiology has been depicted as a scientific approach that moves slowly, but with great force. However, by incorporating the powerful new tools being generated by recent advances in genomics and molecular sciences, epidemiology has an unparalleled opportunity to move more quickly and with greater force than ever. To foster this approach, NCI has designated "molecular epidemiology" as a strategic priority area to meet the director's 2015 challenge goal. Poised to accelerate knowledge about the genetic and environmental components of cancer induction and progression, it will also help identify new preventive, diagnostic, and therapeutic interventions.
An integral feature of this initiative is the planning and development of strategic partnerships that link epidemiologists with one another and with genomicists and other investigators from the clinical, basic, and population sciences. 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.
The study designs should have the efficiencies and power to identify common low-penetrant susceptibility genes and their interactions with exogenous or endogenous exposures gleaned from questionnaires and biospecimen collections. 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 now 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 unique partnership is the Consortium of Cohorts, an international collaboration of intramural and extramural investigators responsible for 23 independently funded population cohorts encompassing 1.2 million individuals. Each cohort has extensive information on known or suspected risk factors as well as biospecimens (including germline DNA) collected prior to diagnosis of cancer, and each has (or will soon have) thousands of individuals who have developed cancer. Through a joint planning process, this consortium provides an integrative framework for nested case-control studies of specific cancers arising within the cohorts to systematically evaluate molecular and biochemical biomarkers of susceptibility and early-stage disease.
On Feb. 10-11, members of the consortium met at NIH to discuss progress and future directions. A status report was given for an initial study conducted among 600,000 individuals in 10 cohorts that have the largest number of cancer cases. This study is focusing on the risk of breast cancer (7,000 cases) and prostate cancer (9,000 cases) associated with variations in hormone- and growth factor-related genes, as well as their interactions with risk factor data and circulating levels of hormones and growth factors. The meeting also provided an opportunity to discuss new high-throughput genotyping technologies that can be used for candidate gene approaches and genome-wide searches as well as linkage-based studies. This discussion was informed by a presentation by Dr. Francis Collins, director of the Human Genome Research Institute, on the status of the International HapMap Project, which holds promise as a research tool for future studies in genetic and molecular epidemiology.
Other types of strategic partnerships are under development, including case-control consortia that involve investigators responsible for population- or hospital-based case-control studies, with special attention to the less common cancers that cannot be easily evaluated in cohort studies. Intramural and extramural investigators have already joined forces in a coordinated series of ongoing case-control studies focused on non-Hodgkin's lymphoma and on brain tumors. In addition, a number of scientists interested in familial cancer have formed an international family-based consortia. Current emphasis is placed on those familial syndromes where high-penetrant genes have eluded discovery, or where opportunities exist to identify genetic and environmental modifiers of inherited risk. The most recent intramural/extramural partnership of this kind centers on studies of familial chronic lymphocytic leukemia.
There are many complex scientific, administrative, and cultural challenges involved in developing these team-based transdisciplinary partnerships, which seemingly run counter to the traditional model of individual investigators or groups that work independently. However, the two strategies are really complementary and synergistic, speeding the discovery of causal agents and pathways, early detection markers, and interventions designed to prevent and control cancer.