Since over 70 percent of prostate cancer cases are diagnosed at age 65 years or older, aging is suspected to be involved in the development of the disease. However, little is known about the mechanism underlying the link between aging and prostate cancer risk. Aging is a biological process governed by a series of molecular and biochemical changes, many of which are manifested by abnormal increases or decreases in gene expression. Suppression of gene transcription through DNA methylation is an important mechanism in regulation of gene expression, and DNA methylation in certain genes increases with age. DNA methylation has also been found frequently in cancer, and many genes with important functions against malignant transformation, such as tumor suppressor genes, detoxification genes, and DNA repair genes, are silenced in cancer due to methylation. The parallel of methylation-suppressed gene expression in the elderly and in cancer patients suggests that DNA methylation may explain in part the increased risk of prostate cancer seen in older men. Despite this observation, no epidemiologic evidence exists concerning the hypothesis that age-related systemic increases in DNA methylation in tumor suppressor genes, detoxification genes, and DNA repair genes occur, and that these increases relate to prostate cancer risk. In this proposal, we will examine this hypothesis by determining if: a) CpG island promoter methylation is increased with age in a tumor suppressor gene, a detoxification gene, and a DNA repair gene; b) CpG island methylation in these genes is higher in African-Americans than in Caucasians; c) CpG island methylation in these genes is higher in prostate cancer patients than in age- and race-matched healthy controls; and d) CpG methylation in these genes is associated with other age-related biomarkers. To achieve these goals, we will analyze blood samples collected from 1,697 men who participated in a prostate cancer screening program during 1998-2000. Plasma and peripheral blood cell DNA will be analyzed for DNA methylation using methylation-specific PCR. Plasma biomarkers will be analyzed using ELISA. The findings of this study will provide insights into the possible mechanism between aging and prostate cancer and may lead to development of new markers.
