Prostate cancer (PCa) is the most common noncutaneous cancer diagnosed in men in the United States. It is now well established that the incidence and associated mortality and morbidity from PCa shows ethnicity specific disparity, African Americans being disproportionately affected. One major challenge related to management of PCa patients is the variable and often indolent nature of the disease progression. It is difficult to predict whether men diagnosed with PCa will develop aggressive cancer if left untreated or treated with an approach less aggressive than surgery. Most deaths and disabilities from PCa are attributable to the metastatic phase of the disease, for which currently there is no curative therapy. The molecular and cellular underpinnings of PCa metastasis remain poorly understood, multiple-hits acquired from somatic genetic alterations are considered to be important contributing factor. The central hypothesis of this project is that comparing normal, primary and metastatic cancerous prostate tissues from the same patient can identify somatic mutations driving metastasis of PCa. To test this hypothesis, we propose two specific aims for this study: (i) to perform whole exome sequencing of normal, primary tumor and metastatic prostate cancer tissue from 20 African American patients to identify somatic risk variants, mapping the mutated genes and identifying candidates for metastasis; and (ii) To perform in vitro functional characterization of two top-ranked genes identified from specific aim 1 using forced overexpression and knockdown approaches to evaluate their mechanistic impact in driving PCa metastasis. Results from this study will lead to the advancement in our current understanding on the genetic underpinnings of PCa metastasis. PCa metastasis specific biomarkers identified from the results of this study have the potential to be used clinically to screen for, diagnose or monitor the progression of PCa and to guide molecular targeted therapy or assess therapeutic response. Findings from this study may not only be usefully informative for African Americans, but can also provide more generalizable insights into this disease.
This proposal is designed to study the underlying genetic factors for prostate cancer metastasis in African Americans who are known to be disproportionately affected by the disease with poor outcomes. By whole exome sequencing of normal, primary and metastatic cancer tissue from same patient, we will identify genes/pathways driving prostate cancer metastasis. We will then examine the biological role of two top-tier genes in cancer metastasis.