Identification and Validation of DNA Methylation Biomarkers for High Grade and/or

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Prostate cancer recurrence after treatment continues to be the major cause of prostate cancer related morbidity and mortality. Since only a relatively small subset of men that develop prostate cancer will ever progress to life-threatening disease, the development of biomarkers that can reliably predict which men with prostate cancer are likely to develop aggressive and/or recurrent cancer would have tremendous clinical and translational value. The progressive acquisition of somatic genome alterations is a defining feature of all human cancers, including prostate cancer. Cancer cells carry a variety of genetic defects, including mutations, deletions, translocations, and amplifications. More recently, we and others have shown that cancer cells also acquire a number of epigenetic defects, including changes in DMA cytosine methylation patterns, 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 epigenetic processes, appears to occur in multiple waves. A large initial wave of CpG island hypermethylation appears to occur very early during prostate carcinogenesis, arising at the stage of prostate precursor lesions and maintained throughout disease progression. These early CpG island hypermethylation changes are already under large-scale clinical and translational development as biomarkers for prostate cancer screening and diagnosis. We and others have also collected preliminary evidence suggesting that there are subsequent waves of CpG island hypermethylation in prostate cancer, and that these changes, which may play a role in driving disease progression, may be associated with disease severity (e.g., cancer grade and stage) and/or recurrence after treatment. In this project, we hypothesize that CpG island hypermethylation changes occurring in these susbsequent waves can be exploited as reliable DNA based molecular biomarkers for aggressive (i.e., high grade) and/or recurrent prostate cancer. We plan to undertake the most comprehensive genome-wide search and large-scale epidemiologic study-based validation of such DNA methylation biomarkers in prostate cancer to date in two specific aims. In the first aim, we will carry out a high-resolution, genome-wide characterization of DNA methylation changes in high grade and/or recurrent prostate cancers using a novel genome-wide DNA methylation detection technology developed in our laboratory. In the second aim, we will perform large scale validation of previously known and newly identified DNA methylation changes as biomarkers of high-grade and/or recurrent prostate cancer using two large epidemiologic studies. These studies will evaluate the utility of DNA methylation alterations as biomarkers of prostate cancer risk stratification.