Johns Hopkins Molecular and Cellular Characterization Laboratory (Prostate)

Together this work will yield highly relevant information that can be directly applied to the clinical management of localized prostate cancer. Specifically, it will yield an integrated signature that distinguishes localized - indolent tumors from localized tumors with lethal potential. Additionally we believe these signature will be critical in determining treatment strategies for individuals with prostate cancers of indeterminate kinetics.
Aim 1: Develop Integrated Genomic, Epigenomic and Expression Profiling Signatures of Indolent and Aggressive Prostate Cancer from both White and African-American Men. Using a discovery set of enriched fresh frozen prostate cancer lesions, we will use Next Generation DNA sequencing to perform genome wide profiling of indolent (Gleason grade 6) and aggressive (Gleason grade 8-10) cancers, separately procured from both White and African American men that includes: mRNA (RNAseq), DNA methylation changes (qMDBseq), variant/mutation and copy number alterations (whole exome sequencing), and genomic rearrangements (low pass whole genome sequencing). We will then apply state of the art bioinformatics approaches for data analysis to determine the number and extent of changes and then perform integrated data analysis to develop molecular signatures that accurately separate indolent from aggressive lesions. Once molecular/pathway alterations are discovered we will prioritize biomarkers/signatures based on whether they correlate with Gleason grade, using both solution-based multiplex profiling as well as in situ based technologies to determine cell type specific alterations. Further, we will also characterize the heterogeneous nature of key changes, as well as determine whether such changes occur primarily in tumor cells or within nontumor microenvironmental cell types. <br><br>Aim 2: Validate Biomarkers and Pathways in Active Surveillance and Autopsy Patients. Markers obtained from the preliminary validation phase from Aim 1 will be used for validation by immunohistochemistry (IHC) and/or in situ hybridization (ISH) on a number of datasets. The first is a large active surveillance cohort of ~1100 men serially biopsied and followed expectantly, and the second is a TMA available from the Baltimore Longitudinal Study of Aging observational cohort generated at autopsy from men who died with either indolent or aggressive prostate cancer.<br><br>Aim 3: Validate Biomarkers in Relation to Patient Outcome, with Emphasis on Intermediate Risk and African American Patients. Further validation will be done with IHC and ISH on multiple highly annotated prostate cancer specific outcome datasets using TMAs from JHU (both existing and to be developed) as well as the Harvard health Professionals and Physician Health Study datasets.
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