Genetic Susceptibility To Carcinogens

Environmental Health Sciences

Investigators

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Abstract

Background. Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to environmentally induced disease. 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 15,000 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), XRCC1, XPD, vary significantly between Asians, European- 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. Mission: Our long-term goal is to understanding how genes and environment interact to influence risk of environmentally induced disease. To this end we are engaged in "Environmental Genomics." This encompasses: 1) identification of candidate environmental response genes, 2) discovery and functional characterization of genetic and phenotypic variation in these genes, and; 3) the analysis in population studies of environmental disease susceptibility associated with functional polymorphisms, acquired susceptibility factors and exposures; and the interactions between these factors. Eventually we hope these genomic approaches will help us to develop assays using genotype, gene expression, and other biomarkers of exposure and effect, that will be predictive of future risk. This information will allow us to more carefully determine the bounds of human variability in risk assessment and will be useful in developing prevention strategies to reduce disease incidence. The Genetic Susceptibility Project takes the candidate susceptibility factors from the laboratory genotype/phenotype studies and tests them in population studies. We are collaborating with numerous NIH, and university-based epidemiology groups to design and carryout appropriate tests of these factors in population-based epidemiology studies. Progress/accomplishments: 1. NAT2 slow acetylation and bladder cancer in workers exposed to benzidine This study expands a previous study of NAT2 polymorphisms and bladder cancer in male subjects occupationally exposed only to benzidine. The combined analysis of 68 cases and 107 controls from a cohort of production workers in China exposed to benzidine included 30 new cases and 67 controls not previously studied. NAT2 enzymatic activity phenotype was characterized by measuring urinary caffeine metabolite ratios. PCR-based methods identified genotypes for NAT2, NAT1 and GSTM1. NAT2 phenotype and genotype data were consistent. A protective association was observed for the slow NAT2 genotype (bladder cancer OR = 0.3; 95% CI = 0.1 = 1.0) after adjustment for cumulative benzidine exposure and lifetime smoking. Individuals carrying NAT1wt/*10 and NAT1*10/*10 showed higher relative risks of bladder cancer (OR = 2.8, 95% CI = 0.8-10.1 and OR = 2.2, 95% CI = 0.6-8.3, respectively). No association was found between GSTM1 null and bladder cancer. A metaanalysis risk estimate of case-control studies of NAT2 acetylation and bladder cancer in Asian populations without occupational arylamine exposures showed an increased risk for slow acetylators. The lower limit of the confidence interval (OR = 1.4; 95% CI = 1.0-2.0) approximated the upper confidence interval for the estimate obtained in our analysis. These results support the earlier finding of a protective association between slow acetylation and bladder cancer in benzidine-exposed workers, in contrast to its established link as a risk factor for bladder cancer in people exposed to 2-naphthylamine and 4-aminobiphenyl. Study findings suggest the existence of key differences in the metabolism of mono- and diarylamines. Glutathione S-transferase polymorphisms and survival from head and neck cancer BACKGROUND: The purpose of this study was to evaluate the prognostic ability of polymorphisms of three genes involved in the metabolism of tobacco carcinogens (GSTT1, GSTM1, GSTP1) and one polymorphism of a DNA repair gene (XRCC1) for patients diagnosed with squamous cell carcinoma (SCC). METHODS: Cox proportional hazard models were used to estimate risk of death for a prospective cohort of 190 patients. RESULTS: Individuals with the GSTT1 functional genotype were twice as likely to die from any cause (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.13-4.97) and were three times as likely to die from SCC (HR, 3.4; 95% CI, 1.33-8.41) after adjustment for age, primary therapy, and stage of disease. The XRCC1 399 Gln genotype was predictive of disease recurrence. CONCLUSIONS: Our findings, from one of the first studies to examine this research question, suggest that genomic markers of carcinogen metabolism and DNA repair capability may serve as prognostic indicators of disease recurrence and death.