Summary of Work: Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to cancer. The group has developed genotyping assays for the "at-risk" variants of enzymes that protect against carcinogens in cigarette smoke, diet, industrial processes and environmental pollution. Following genotyping of over 5000 individuals for these candidate susceptibility genes, it has been found that the frequency of the at-risk genotypes for glutathione transferase M1 (GSTM1), theta 1 (GSTT1), Pi (GSTP1) and n-acetyltransferase (NAT1 and NAT2) vary significantly between Asians, Caucasian- and African-Americans. This suggests that some of the ethnic differences in cancer incidence may be due to genetic metabolic differences as well as exposure differences. In ongoing studies with researchers at the NIEHS, National Cancer Institute, Columbia Univ., Johns Hopkins Univ., Univ. of North Carolina and Univ. of Occupational and Environmental Health, Japan, the group is testing the impact of these cancer susceptibility genes in case-control studies of cancer of the bladder, lung, liver, colon, stomach, prostate, breast and myelodysplastic syndromes. The glutathione transferase M1 (GSTM1) gene defect has recently been shown to be a risk factor among Japanese gastric cancer patients who were also smokers (6). It was found that both genetic and nutritional factors modulate levels of DNA damage observed among heavy smokers (5). It was observed that a vitamin D receptor polymorphism was associated with risk of prostate cancer (7). The presence of the GSTT1 gene was determined to be an crucial factor in dichloromethane metabolism to formaldehyde in human liver(11). These studies seek to integrate environmental and genetic factors in understanding the etiology of human disease.