Molecular Genetics of NAT1 and NAT2 in Prostate Cancer

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DESCRIPTION (provided by applicant): In the United States, prostate cancer is the most common form of cancer and is the second leading cause of cancer-related death among men. It is estimated that 220,900 new cases of prostate cancer will be diagnosed and that approximately 28,900 men will die of the disease in 2003. African-American men have the world's highest incidence of prostate cancer and more than twice the death rate compared with Caucasian men. African-American prostate cancer patients also have significantly higher rate of severity at diagnosis. The differences in race and family history of prostate cancer suggest that genetic factors play an important role in causing prostate cancer. Human N-acetyl-transferase 1 and 2 (NAT) are very important enzymes involved in the metabolism of a variety of carcinogenic compounds and are postulated to play a critical role in the development of prostate cancer. Our preliminary data has shown that elevated NAT2 enzyme activity is strongly associated with increased risk of prostate cancer in both Caucasian and African-American men. However, the genetic factors contributing to high NAT2 enzyme activity remain under-explored. This research is proposed to systematically investigate the genetic reasons responsible for high NAT activity that contribute to high incidence of prostate cancer. The promoter regions (a fragment of DNA involved in controlling gene expression) along with the coding and 3'UTR regions of NAT1 and 2 will be examined and all mutations/polymorphisms will be mapped. The specific combinations of mutations will be categorized and characterized and the correlation between mutation combinations and high NAT2 enzyme activity will be analyzed. In this manner, specific pattern(s) of mutations that are highly associated with high NAT2 activity will be defined. Finally, the specific pattern(s) of mutations will be measured in 111 African-American and 353 Caucasian prostate cancer patients, as well as in the same number of race and age matched controls. Statistical analysis will be conducted to assess which patterns of mutations are associated with prostate cancer susceptibility. We envision, upon completion of this study, that potential biomarker(s) (specific patterns of NAT1 and 2 mutations) for increased odds of prostate cancer would be identified.