Impact of Adduct Determination on the Assessment of Cancer Susceptibility
The characterization of genetic determinants for cancer susceptibility is important for understanding disease pathogenesis and for preventive measures. There is growing evidence that a group of predisposing polymorphic genes exists, such as those involved in carcinogen metabolism and repair, which may increase cancer in certain environmentally exposed subjects, even those exposed only to low levels of carcinogens. In developing preventive strategies, it is therefore necessary to identify these vulnerable members in our society, particularly those suffering from an unfortunate combination of high carcinogen exposure, cancer-predisposing genes and lack of protective (dietary) factors. Thus, molecular epidemiology faces the difficult task of analyzing carcinogen-exposed individuals for a combination of genotypes associated with cancer susceptibility. Once identified, combinations of cancer-predisposing genes can then be used as intermediate risk markers rather than taking cancer as an endpoint. In case-control studies, simultaneous measurements were carried out in each subject to determine exposure/early effect markers, e.g. polycyclic aromatic hydrocarbons (PAH)-DNA adducts, and susceptibility markers, e.g. genetic polymorphism, in drug-metabolizing enzymes related to cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase (GSTM1) genes. The genotype dependence of human lung (+)-antibenzo[a]pyrene diol-epoxide (BPDE)-DNA adducts in lung cancer patients was examined. BPDE-DNA adduct levels in bronchial tissue of smokers with high pulmonary CYP1A1 inducibility (by immunohistochemistry) and GSTM1 inactive were ~100-fold higher than in subjects with an active GSTM1 at similar smoking dose. Further genetic analyses confirmed that the combination of CYP1A1 homozygous mutants and GSTM1 inactive leads to high levels of BPDE-DNA adducts in human lung of smokers and white blood cells of PAH-exposed coke oven workers. Thus, BPDE-DNA adduct levels resulting from the “at risk” genotype combinations may serve as markers to identify high-risk subjects among smokers and individuals occupationally and/or environmentally exposed to PAH.
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