Prostate cancer has become the most commonly diagnosed cancer in men in the United States as well as one of the leading causes of cancer deaths. Unfortunately, the etiology of prostate cancer has not been established. Furthermore, few of the molecular events associated with prostatic carcinogenesis have been elucidated. Epidemiological studies have clearly indicated environmental factors such as the diet and the pathogenesis of life-threatening prostate cancers. However, the molecular mechanisms underlying the role of the environment in fostering prostate cancer development remain obscure. A somatic genetic alteration associated with prostatic carcinomas might provide mechanistic hypotheses to account for the role of the environment in the US prostate cancer epidemic if the alteration: 1) occurred uniformly in all of the prostate cancer cases; 2) arose early during prostatic carcinogenesis; and 3) involved the locus of a gene plausibly associated with the susceptibility to carcinogenic factors in the environment. Such an alteration might also serve as a valuable biomarker for prostate cancer diagnosis staging and treatment monitoring. Preliminary studies from Dr. Nelson's laboratory have identified a new genomic alteration, hypermethylation of """"""""CpG island"""""""" sequences in the regulatory region of the p- class glutathione S-transferase gene (GSTP1), that has been detected in all human prostate cancer specimens thus far analyzed. The genomic change appears to be accompanied by lack of GSTP1 expression giving rise to the hypothesis that a deficiency in GSTP1 enzyme activity might render normal prostatic epithelial cells vulnerable to transformation and neoplastic prostatic cells vulnerable to malignant progression upon exposure to electrophillic carcinogens. Dr. Nelson's proposed project studies aim to begin to test this hypothesis: 1) by mapping the region of the """"""""CpG island"""""""" near the GSTP1 gene in normal cells using a genomic sequencing strategy, 2) by using this genomic sequencing approach to determine the extent of cancer specific GSTP1 promoter methylation changes, 3) by developing methodologies for detecting and fully characterizing GSTP1 promoter methylation changes using the polymerase chain reaction, 4) by evaluating prostate cancer precursor lesions and familial prostate cancer tissue specimens for loss of GSTP1 expression and somatic GSTP1 gene changes, and 5) by assessing the functional consequences of loss of GSTP1 expression on the sensitivity of prostatic cell DNA to genotoxic agents.
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