INTERACTIONS BETWEEN GENETIC PREDISPOSITION AND ENVIRONMENTAL TOXICANTS FOR DEVELOPMENT OF LUNG-CANCER

Significant interindividual variations in health outcome may be caused by the inheritance of variant polymorphic genes, such as CYP2D6 and C YP2E1 for activation, and GSTM1 and GSTT1 for detoxification of chemic als. However. mechanistic studies linking the inheritance of predispos ing genes with genotoxic effects towards cancer have yet to be systema tically conducted. We have studied 54 lung cancer patients and 50 matc hed normal controls, who have been cigarette smokers, to elucidate the role of polymorphic genes in cancer. Our data indicates that the inhe ritance of unfavorable CYP2D6, CYP2E1, and GSTT1 genes is strongly cor related with the smoking-related lung cancer. For heavy cigarette smok ers (> 30 pack-years), the smoking habit is the strongest predictor of lung cancer risk irrespective of the inheritance of unfavorable metab olizing genes. For moderate to light smokers (< 30 pack-years), the ge netic predisposition plays on important role For the risk (odds ratio = 3.46; 95% CL = 0.46-40.2). Using a subgroup of the study population, we observed that cigarette smokers having the defective GST genes hav e significantly more chromosome aberrations as determined by the fluor escence-in-situ-hybridization (FISH) technique than smokers with the n ormal GST genes (P < 0.001). In conclusion, our study provides data to indicate that individuals who have inherited unfavorable metabolizing genes have increased body burden of toxicants to cause increased gene tic damage and to have increased risk for cancer. Studies like ours ca n be used to understand the basis for interindividual variations in ca ncer outcome, to identify high risk individuals and to assess health r isk. (C) 1997 Wiley Liss, Inc.