Markers of dna repair and susceptibility to cancer in humans: an epidemiologic review

Páginas: 25 (6126 palavras) Publicado: 13 de setembro de 2011
Markers of DNA Repair and Susceptibility to Cancer in Humans: an Epidemiologic Review
Marianne Berwick, Paolo Vineis
At least some of such interindividual difference is likely to have a genetic origin. A number of epidemiologic studies have been conducted to compare measures of DNA repair capacity between cancer case subjects and healthy control subjects to assess the role of repair inthe development of human cancer. Such studies have used a variety of measures of DNA repair capacity. However, DNA repair capacity is extremely complex; at this time, the current assays do not measure specific aspects of repair but rather assess more global effects. Most assays are based on an approach that compares induced DNA damage to circulating lymphocytes from subjects with cancer withinduced DNA damage to circulating lymphocytes from subjects without cancer with quantitation of subsequent “repair” in both groups. Damage is usually delivered in the form of a “pulse” of carcinogen applied to cell culture (e.g., -rays, UV radiation, benzo[a]pyrene diol epoxide [BPDE], or hydrogen peroxide [H2O2]) or to fresh or cryopreserved lymphocytes. A period of time is allowed to elapse forrepair to occur, and then damage is measured in a variety of ways (e.g., as unrepaired single- or double-strand breaks or the rate of incorporation of a radioisotope). We have attempted a formal evaluation of the published studies of DNA repair capacity in the etiology of human cancer and have considered their design, methods, and results. In addition, we have assessed the results and the limitationsof such studies. We use the term “DNA repair capacity” to describe a variety of different techniques and manifestations, not all of which are necessarily a direct expression of actual repair of DNA damage but are often a measure of unrepaired DNA damage.

DNA repair is a system of defenses designed to protect the integrity of the genome. Deficiencies in this system likely lead to the developmentof cancer. The epidemiology of DNA repair capacity and of its effect on cancer susceptibility in humans is, therefore, an important area of investigation. We have summarized all of the published epidemiologic studies on DNA repair in human cancer through 1998 (n = 64) that addressed the association of cancer susceptibility with a putative defect in DNA repair capacity. We have considered studydesign, subject characteristics, potential biases, confounding variables, and sources of technical variability. Assays of DNA repair capacity used, to date, can be broadly grouped into five categories: 1) tests based on DNA damage induced with chemicals or physical agents, such as the mutagen sensitivity assay, the G2-radiation assay, induced micronuclei, and the Comet assay; 2) indirect tests of DNArepair, such as unscheduled DNA synthesis; 3) tests based on more direct measures of repair kinetics, such as the host cell reactivation assay; 4) measures of genetic variation associated with DNA repair; and 5) combinations of more than one category of assay. The use of such tests in human populations yielded positive and consistent associations between DNA repair capacity and cancer occurrence(with odds ratios in the range of 1.4–75.3, with the majority of values between 2 and 10). However, the studies that we have reviewed have limitations, including small sample size, “convenience” controls, the use of cells different from the target organ, and the use of mutagens that do not occur in the natural environment. The evolving ability to study polymorphisms in DNA repair genes maycontribute to new understandings about the mechanisms of DNA repair and the way in which DNA repair capacity affects the development of cancer. [J Natl Cancer Inst 2000;92:874–97] Interindividual variability in human responses to carcinogens has been described repeatedly. Much attention has been devoted to heritable polymorphisms in genes involved in carcinogen metabolism. Another potentially important...
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