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 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 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, etc 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. Aims: 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 Environmental Genomics Section is testing the impact of these cancer susceptibility genes in case-control studies of cancer of the bladder, skin, lung, liver, colon, stomach, prostate, and breast. Accomplishments: 1. We examined the association of polymorphisms in XRCC1 (Arg194Trp, Arg399Gln) and breast cancer in the Carolina Breast Cancer Study. No association was observed between XRCC1 codon 194 genotype and breast cancer. Exposure to ionizing radiation was associated with breast cancer among women with XRCC1 codon 399 Arg/Arg genotype. Our results suggest that XRRC1 codon 399 genotype may influence breast cancer risk, perhaps by modifying the effects of environmental exposures (1). 2. Squamous cell carcinoma of the head and neck (SCCHN) is strongly associated with alcohol consumption. We genotyped SCCHN cases and controls for ADH3 alleles. The joint effects of lifetime alcohol use and the presence of the ADH3 'rapid' allele (ADH3*1) was evaluated with adjustment for tobacco use, age, sex and race. The risk of SCCHN was increased nearly 6-fold with consumption of 40 or more alcoholic beverages per week (OR = 5.9, 95% CI 2.0-17.7). However, there was no suggestion of an interaction between any alcohol use variable and the ADH3*1 genotype(2). 3. We tested the interaction between tobacco use and risk of SCCHN in relation to the polymorphisms of GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1. No increased risk was observed for any genotype. However, there was a suggestion of an interaction between tobacco use and the GSTT1 null genotype. NAT1*10 genotypes also had a possible interaction with tobacco smoking history. This study suggests a possible gene-environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed (3). 4. Ethylene oxide (EO) formed during metabolism of cigarette smoke produces adducts in erythrocytes. We tested whether null genotypes for glutathione transferase (GSTM1 and GSTT1) alter the internal dose of EO in 16 nonsmokers and 32 smokers (one to two packs/day). HEVal levels were significantly elevated in GSTT1-null individuals when normalized to smoking status or cotinine levels. The lack of a functional GSTT1 is estimated to increase the internal dose of EO derived from cigarette smoke by 50-70%(4). Significance: These studies seek to integrate environmental and genetic factors into our understanding of the etiology of human disease.