Prostate cancer recurrence after treatment continues to be the major cause of prostate cancer relatedmorbidity and mortality. Since only a relatively small subset of men that develop prostate cancer will everprogress to life-threatening disease, the development of biomarkers that can reliably predict which men withprostate cancer are likely to develop aggressive and/or recurrent cancer would have tremendous clinical andtranslational value. The progressive acquisition of somatic genome alterations is a defining feature of allhuman cancers, including prostate cancer. Cancer cells carry a variety of genetic defects, includingmutations, deletions, translocations, and amplifications. More recently, we and others have shown thatcancer cells also acquire a number of epigenetic defects, including changes in DMA cytosine methylationpatterns, which can have functional equivalence to genetic changes in maintaining malignant phenotypes.For prostate cancer, DNA hypermethylation at CpG islands, one of the most widely studied epigeneticprocesses, appears to occur in multiple waves. A large initial wave of CpG island hypermethylation appearsto occur very early during prostate carcinogenesis, arising at the stage of prostate precursor lesions andmaintained throughout disease progression. These early CpG island hypermethylation changes are alreadyunder large-scale clinical and translational development as biomarkers for prostate cancer screening anddiagnosis. We and others have also collected preliminary evidence suggesting that there are subsequentwaves of CpG island hypermethylation in prostate cancer, and that these changes, which may play a role indriving disease progression, may be associated with disease severity (e.g., cancer grade and stage) and/orrecurrence after treatment.In this project, we hypothesize that CpG island hypermethylation changes occurring in these susbsequentwaves can be exploited as reliable DNA based molecular biomarkers for aggressive (i.e., high grade) and/orrecurrent prostate cancer. We plan to undertake the most comprehensive genome-wide search andlarge-scale epidemiologic study-based validation of such DNA methylation biomarkers in prostate cancer todate in two specific aims. In the first aim, we will carry out a high-resolution, genome-wide characterization ofDNA methylation changes in high grade and/or recurrent prostate cancers using a novel genome-wide DNAmethylation detection technology developed in our laboratory. In the second aim, we will perform large scalevalidation of previously known and newly identified DNA methylation changes as biomarkers of high-gradeand/or recurrent prostate cancer using two large epidemiologic studies. These studies will evaluate theutility of DNA methylation alterations as biomarkers of prostate cancer risk stratification.
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