Prostate cancer is the most commonly occurring cancer in U.S. men. African American men have the highest prostate cancer rate in the world. There is relatively little information available about the etiologic factors that may explain these rates. The objective of the present study is to examine the role of genes that regulate the disposition of testosterone in prostate cancer etiology, and to evaluate whether these genes explain, in part, differences in prostate cancer rates between African Americans and U.S. Caucasians. These genes include the cytochromes P450 CYP3A4 and CYP19, 5alpha-reductase II (SRD5A2), androgen receptor (AR), and the type II 3beta-hydroxy-steroid dehydrogenase (HSD3beta2). All of these genes are involved in the downstream metabolism of testosterone, and thus focus our hypotheses on a relevant, defined set of metabolic pathways.
Three specific aims are proposed here.
In Specific Aim 1, we will systematically evaluate allelic and genotypic distributions at these candidate genes, and compare these distributions in four ethnic groups (Ghanaian, Senegalese, African American, and US Caucasian men). In addition, obtaining data from Ghana and Senegal will initiate collaborations to foster formal studies of prostate cancer etiology in Africans.
In Specific Aim 2, we propose to undertake both case-case and case-control analyses to evaluate the relationship of candidate genotypes with prostate cancer in African Americans.
In Specific Aim 3, we propose to evaluate differences in the genotype-prostate cancer relationship between African Americans and Caucasians. We will again use case-case and case-control designs to evaluate differences in prostate cancer etiology between these two groups. In order to address these hypotheses, we will undertake a study using an existing subject accrual system to identify a sample of 800 incident prostate cancer cases and 800 controls. Half of these will be African American and half will be Caucasian. A sample of healthy Ghanaian and Senegalese controls will also be accrued. Risk factor information will be obtained from a questionnaire interview, a biosample containing DNA will be collected using a non-invasive cheek swab method, and pathology information will be collected using a standardized medical record abstraction approach. An understanding of the complex interplay of genetic variability at multiple loci and of environmental agents may improve our understanding of prostate cancer etiology and risk prediction. This information could then be used to more effectively apply prostate cancer prevention and control strategies.
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