African American men experience a disproportionate burden of aggressive prostate cancer and prostate cancer mortality when compared with white men. The underlying reason for the disparity is unclear and the ability to predict an individual patient's disease trajectory remains limited. This makes treatment decisions difficult, particularly as available treatments range widely from active surveillance to radical prostatectomy, which can have severe consequences such as urinary incontinence and erectile dysfunction. There is growing evidence to support the potential of DNA methylation (DNAm) and RNA expression markers in prostate tumors to enhance prostate cancer prognostication beyond clinical factors, but few studies to date have focused on African American men. The present pilot study will leverage a unique patient population (>40% African American) and archival radical prostatectomy prostate tissue from the University of Maryland Greenebaum Comprehensive Cancer Center.
Aims 1 and 2 propose to leverage array-based technology to investigate whether DNAm and RNA expression markers can discriminate between aggressive (total Gleason score>7) and non-aggressive prostate cancer (total Gleason<7) in African American men. We will use Gleason score as our endpoint because it is available for all samples and because recent studies have supported its utility as an intermediate endpoint in the discovery of prognostic markers.
Aim 3 proposes integrated analyses of DNAm and RNA expression data to investigate the hypothesis that some DNAm markers are associated with aggressive disease independently of expression, thereby providing unique prognostic information. The K07 mechanism will allow me to receive essential training in the integration/application of tumor tissue biomarkers in epidemiological studies and analysis of high-dimensional data under the guidance of a strong team of mentors with synergistic expertise in molecular epidemiology, prostate tumor biomarkers, bioinformatics/computational genomics, and statistics (Drs. Joanne Dorgan, Lorelei Mucci, Hctor Corrada Bravo and Sren Bentzen). Dr. Arif Hussain, a genitourinary oncologist and basic science researcher in prostate cancer, will serve as an additional advisor and contribute to the interpretation and assessment of clinical significance of findings. My previous research has focused on blood-based biomarkers in targeted genomic regions and I will greatly benefit from specialized training in tumor tissue markers and expanding to high-dimensional data as I move towards independence in molecular cancer epidemiology. Moreover, this study will provide preliminary data that will build toward a larger (R01) application in which I will integrate epigenomic and transcriptomic data for the discovery of novel biomarkers of aggressive prostate cancer among African American men. My long-term goal is to lead studies that will promote improved public health and reduce disparities in cancer outcomes through personalized medicine.
The overall public health objective of this proposed study is to identify biomarkers that will improve risk- stratification for African American men with prostate cancer, who bear a disproportionate burden of aggressive disease and prostate cancer mortality, but have been underrepresented in previous studies. This research, in turn, will allow for more personalized treatment/management strategies that have potential to improve patient outcomes and reduce disparities in prostate cancer mortality.
