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Cancer Risk and Low-Penetrance Susceptibility Genes in Gene-Environment Interactions

From the Cancer Genetics and Epidemiology Program, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC; and Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Address reprint requests to Curtis C. Harris, MD, Laboratory of Human Carcinogenesis, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bldg 37, Rm 2C01, 37 Convent Dr, MSC 4255, Bethesda, MD 20892-4255; email Curtis_Harris@ nih.gov.

ABSTRACT

PURPOSE: To provide a concise review for human cancer risk related to low-penetrance genes and their effects on environmental carcinogen exposure.

METHODS: Citation of relevant and recent references for molecular epidemiology, focusing on lung cancer, ethical issues, and some clinical implications of recent molecular epidemiology studies.

RESULTS: Low-penetrance genes contribute to cancer risk by augmenting the effects of carcinogen exposures. These exposures can be measured in the body through molecular dosimetry (ie, the amount of DNA damage), which reflects a biologically effective dose. The examination of tumors and the mutations within tumor suppressor genes, such as p53, can provide etiologic clues for both exposure and susceptibility. Although many studies have focused on carcinogen metabolism and cancer risk, more recent studies are considering DNA repair. Also, we are learning that behavior, such as tobacco addiction, also may be genetically controlled.

CONCLUSION: Sporadic cancers are caused by geneⁿ-environmentⁿ interactions rather than a dominant effect by a specific gene, environmental exposure, or gene-environment interaction. New paradigms, where we categorize genes as caretaker or gatekeeper genes, will allow for new hypotheses to be tested and will require advanced methods of analysis. The goal of molecular epidemiology is to develop risk assessment models for individuals, but currently the most achievable goal will be population risk assessment and a better understanding of carcinogenesis.

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