Molecular Epidemiology

Classic or traditional epidemiology, as discussed previously, permits epidemiologists to evaluate risks and environmental causality in cancer. Molecular epidemiology, a hybrid of epidemiology and molecular genetics, enables researchers to assess biologic characteristics influencing cancer susceptibility. The combination of epidemiologic approaches and bench science has effectively "broken open the black box of epidemiology," a discipline historically left to speculate as to the biologic mechanisms underlying its detected exposure-disease associations.14,15 The concept that risk of cancer from a given exposure differs between subgroups of a population is an example of what is known in the epidemiologic vernacular as effect modification. Biostatisticians often refer to this heterogeneity of effect as interaction. With the advent of polymerase chain reactions and other advanced laboratory methods, epidemiologists incorporating molecular markers into their studies can begin to identify specific suspect endogenous or exogenous host factors at the biochemical or molecular level that put individuals at considerably higher (or lower) cancer risk.16

Molecular epidemiologic studies aim to determine the roles, including interactions, of environmental and genetic factors in the initiation and progression of cancer. Incorporating genetic markers in epidemiologic studies of cancer etiology shows promise for revealing details of carcinogenic pathways that can provide strategies for prevention and, ultimately, reduce cancer risk. Although the promise for critical advances in understanding cancer is great, molecular epidemiology faces important challenges, such as ensuring the appropriate interpretation of molecular testing and resolving associated ethical, legal, and social concerns.

The use of molecular epidemiology to identify biomark-ers also may provide useful information on the extent of exposure to carcinogens and cancer risk. Perera and Wein-stein15 delineated four characteristics important for biomark-ers to predict risk: internal dose, biologically effective dose, response, and susceptibility. Describing and determining the occurrence of such suitably selected biomarkers has already advanced research on the mechanisms of cancer initiation and promotion and enabled improved assessment of the cancer risk of healthy individuals. Moreover, the knowledge that gene mutations and changes in their expression underlie carcinogenesis has spurred the hunt for aberrant genes and their associated proteins.

Molecular parameters added to population-based studies should help to identify genes, proteins, and pathways involved in cancer development caused by environmental exposures and susceptible or resistant subpopulations. The exponential growth of scientific technology and information promises rapid expansion of knowledge about the identity of potentially mutant genes and cancer pathways.

As a hypothetical framework for dissecting the development of cancer in individuals, current studies of molecular epidemiology consider both the complex, multistage process of carcinogenesis and heterogeneous responses to carcino genic exposures. Improving continuously, measurements of human exposure to carcinogens have been successfully applied in a number of molecular epidemiologic studies. Inherited and acquired genetic predispositions to cancer have been, and continue to be, identified. Correlating inherited genetic polymorphisms with other cancer risk factors shows considerable promise that molecular epidemiologists will gain in their ability to assess multiple biomarkers and to predict an individual's risk for specific diseases. The field has the near-term potential to impact regulatory quantitative risk assessments, useful in the determination of allowable exposures, and molecular epidemiologic data may also help identify individuals most apt to benefit from cancer prevention strategies.

Molecular epidemiology investigators employ traditional epidemiologic study designs, including case-control and cohort studies that focus on one or more biologic markers that may show an association between exposure and disease outcome. Molecular studies often raise the "nature versus nurture" question, with evidence supporting consensus that gene-environment interplay explains many chronic diseases, including cancer: "Genetics is the loaded gun, and the environment pulls the trigger." Among studies supporting such a statement is a recent large, although statistically limited, study of twins concluding that environment plays a substantial role but requires genetic potential in causing sporadic cancers.16

Molecular epidemiology studies also face the methodological challenges to traditional epidemiologic studies, such as precise measurement of exposure and effects, appropriate selection of study samples, and reduction of the influence of confounders and potential competing risk factors. One important issue is assuring an adequate sample size for study because the prevalence of a specific genetic polymorphism or other biomarker under investigation is often either very rare or quite high, either of which situations require a large number of cases to detect an association.17 One approach to this problem is to combine data from several studies, particularly of rare cancers, to obtain adequate statistical power for meaningful conclusions. When sample sizes are modest, especially, caution in interpretation of data or linking findings with further implications is in order.

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