Genetic Susceptibility To Carcinogens and Toxicants

Environmental Health Sciences

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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. Population studies indicate that for these candidate susceptibility genes, 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 ethnic groups. Some differences in cancer incidence among groups 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. [unreadable] Progress/accomplishments:[unreadable] 1) We conducted a nested case-control study within the Physicians Health Study (PHS), a randomized trial of aspirin and BC at relatively modest doses in which baseline (enrollment/untreated) blood samples from incident cases and matched controls were selected from the bank of over 14,000 stored "enrollment" samples (1). The goal was to test the hypothesis that biomarkers in blood of healthy individuals can indicate their susceptibility to lung cancer or detect early disease that would manifest itself years or decades later (1). The biomarkers were selected on the basis of prior data implicating them in lung cancer and included polycyclic aromatic hydrocarbon (PAH)-DNA adducts, PAH-albumin adducts, ras p21 and polymorphisms in GSTM1, GSTP1, NAT1, NAT2, CYP1A1 and CYP2D6 genes. In this nested case-control study, our prior analysis showed that PAH/aromatic-DNA adducts were significant predictors of lung cancer among smokers, but not former or non smokers, and the combined GSTM1 null/GSTP1 Val genotype was significantly associated with lung cancer before and after adjusting for PAH-DNA adducts (1;14). Here we report on the relationship between lung cancer risk and PAH-albumin adducts, the ras p21 oncoprotein, and polymorphisms in the CYP1A1, CYP2D6, NAT1, and NAT2 genes. While not part of our original hypotheses, we also report on the association between the polymorphisms and the other biomarkers (PAH-albumin adducts and the ras p21 oncoprotein).PAH-albumin adducts and ras p21 oncoprotein were not significant predictors of lung cancer, before or after controlling for treatment assignment. Nor were CYP1A1, CYP2D6, NAT1, and NAT2 genotypes significantly associated with lung cancer. The same lack of association was seen when separate analyses were conducted within each of the major histologic groups (SCLC vs. NSCLC). The results for PAH-albumin and ras p21 suggest that these biomarkers are not early predictors of risk.[unreadable] [unreadable] 2) Background: In vitro, human isoenzymes encoded by genes homozygous for the ADH1C*1 or[unreadable] ADH1B*2 alleles metabolize ethanol to acetaldehyde at a faster rate than those homozygous for the [unreadable] ADH1C*2 or ADH1B*1 allele. Because alcohol is a known risk factor for breast cancer, we [unreadable] evaluated the joint association of genetic variants in ADH and alcohol consumption in relation to breast cancer. Methods: A nested case-control study of 321 cases and matched controls was conducted. Five single nucleotide polymorphisms (SNPs) of the ADH1C and ADH1B genes were genotyped. Conditional logistic regression was used to assess odds ratios (OR) and 95% confidence [unreadable] intervals (CI) for each SNP. Haplotype analysis of all 5 SNPs was also undertaken. [unreadable] Results: Among drinkers, the median intake of total alcohol was 13 grams per week (10th to 90th percentiles; 4.5 135.9) in cases and 18 grams per week (10th to 90th percentiles; 4.5-104.1) in controls. Women who drank alcohol tended to be at an increased risk of developing breast cancer compared to those who did not drink (O.R. =1.40, 95% CI 0.97, 2.03), particularly those who were pre-menopausal at the time of breast cancer diagnosis (OR = 2.69, 95% CI: 1.00, 7.26).[unreadable] Of the known functional alleles, breast cancer risk was not significantly increased among carriers of at least one ADH1C*1 or ADH1B*2 allele, when compared to those heterozygous or homozygous for either the ADH1C*2 or ADH1B*1 allele. However, breast cancer risk tended to be lower among women who inherited the ADH1B*896G allele (O.R. = 0.62, 95%CI 0.37, 1.04). Haplotype frequencies were not significantly different between cases and controls. Conclusion: Low levels of alcohol are associated with a modest increase in breast cancer risk that is not altered by known functional allelic variants of the ADH1B and 1C gene. The protective association conferred by the ADH1B*896G allele needs further evaluation.