The aggressiveness of prostate cancer varies widely; some tumors progress to invasive, potentially life-threatening disease whereas others stay latent for an individual's remaining lifetime. Furthermore, tumor aggressiveness appears to differ between ethnic groups, with African-Americans exhibiting the highest morbidity and mortality rates of prostate cancer in the world. One promising explanation for this phenomenon is that genes influencing androgen metabolism--which drives the prostate's growth and differentiation--increase the risk of progressing to aggressive disease. Another possibility is that genes within chromosomal regions that have been identified from linkage analyses increase this risk. We propose investigating both of these possibilities with a case-control study of the relation between candidate genes/regions and the aggressiveness of prostate tumors, as outlined in the following specific aims.
Specific Aim 1. We will investigate the impact on prostate tumor aggressiveness of four candidate genes involved with the androgen pathway. In this aim we will follow up on our promising data on a variant in CYP3A4, and evaluate polymorphisms in three other candidate genes that many affect dihydrotestosterone levels in the prostate. In particular, associations between aggressive prostate cancer and 1) the CYP3A4 variant;, and 2) polymorphisms in three other candidate genes potentially impacting dihydrotestosterone levels in the prostate (i.e., 5 alpha-reductase II, androgen receptor, and CYP17) will be investigated.
Specific Aim 2. We will localize potential prostate tumor aggressiveness genes within candidate regions on chromosomes 5, 7, 10 and 19. Our recent work indicates that there exist relatively strong linkages between prostate tumor aggressiveness (as measured by Gleason score) and these genomic regions. This suggests that these candidate regions may contain genes that affect the progression to aggressive disease. We will undertake this aim with the complementary approaches of allelic association and loss of heterozygosity mapping. To fulfill our aims we will recruit 500 incident cases with aggressive prostate tumors, and 500 age and ethnicity matched controls from the major medical institutions in Cleveland, Ohio. We will extract DNA from case and control biospecimens, and analyze the candidate genes or markers in the chromosomal regions of interest. Then we will evaluate the relation between these genetic factors and aggressive prostate cancer--and potential effect modification by ethnicity. Detecting molecular markers for tumor aggressiveness may supply important insights into the underlying mechanism of disease, provide a valuable screening tool for non-diseased men, and help guide treatment for men diagnosed with prostate cancer.
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