PILOT--SOMATIC ERRORS IN CARCINOGEN METABOLISM

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The genetically determined ability to metabolize carcinogens and procarcinogens is polymorphic. Because of the resulting differences in detoxification of environmental chemicals and/or in activating procarcinogens to carcinogens, these polymorphisms are associated with susceptibility to environmentally-related cancers, such as squamous cell carcinoma of the head and neck. Our hypotheses are that (i) genetic polymorphisms can be detected with regard to glutathione S-transferases mu, theta, pi, and N-acetylation, as well as to components of the cytochrome P450 system (CYP1A1, CYP2E1) in patients with squamous cell carcinoma of the oral cavity and the oropharynx compared to healthy controls, and (ii) these genetic polymorphisms are associated with risk for the development of this type of cancer. In a pilot study of 42 head and neck cancer patients and 42 matched controls we found that the absence of the GSTM1 gene conferred an odds ratio of 3.10 (95% CI=1.24-7.75), and the absence of the GSTT1 gene conferred an odds ratio of 2.18 (95% CI=0.91-5.23) for head and neck cancer. The GSTM1 genotype was absent in 74% of our patients, in contrast to the range of 31-58% published. The absence of the GSTT1 gene was shown in 55% of our patients, in contrast to the published range of 30-40%. A case-control study is proposed, involving 250 patients and 250 healthy individuals (matched by age, gender, race, and smoking status). The genetic status of the study subjects will be determined with regard to glutathione S-transferases mu, theta, and pi, N-acetylation, CYP1A1, and CYP2E1 by PCR-based methodologies, using DNA extracted from peripheral blood lymphocytes (Specific Aim #1). Two approaches will be applied for estimating cancer risk. First, the associations between risk and genetic polymorphisms will be calculated for each polymorphism assayed (Specific Aim #2). Next, this single-factor analysis will be expanded by combining the genotypes into a multifactorial risk model (Specific Aim #3). The study is expected to yield important information about host factors of environmentally-associated carcinogenesis. Testing several genetic polymorphisms simultaneously has the potential to identify individuals with extremely high cancer risk. This has profound implications for prevention: individuals at high risk for cancer can be enrolled into intensive preventive programs not suitable for the general population, including chemopreventive approaches.