Epigenomic Landscape of Primary Prostate Cancer in African American Men
Abstract
African American men are more than twice as likely to die from prostate cancer as their non-Latino White counterparts. Though access to healthcare certainly contributes to this cancer health disparity, it is increasingly clear that there are important biological differences between prostate tumors arising in African American and White patients. Most biological studies to date have focused on tumor DNA sequencing, which has paradoxically shown that DNA alterations associated with poor outcomes in White patients are actually less common in prostate tumors from African American patients. This suggests that many of the DNA changes used to predict prognosis may be useful in a smaller fraction of African American patients, and new biomarkers of aggressive prostate cancer are needed for African Americans. These studies make it clear that we must move beyond the simple sequence of DNA to understand why African American prostate cancer is more aggressive. Epigenomic alterations to the DNA are chemical modifications, such as chemical tags called methyl groups, that do not alter the DNA sequence of the genes, but have powerful effects on the cell by turning genes off or on. Interestingly, these modifications to DNA can occur in response to changes in the environment of the cell, enabling the cell (or tumor) to adapt to changing conditions. Though we know that epigenomic alterations are very important in prostate cancer progression and can be as stable as changes in the DNA sequence, very few studies have comprehensively looked at these changes in African American prostate cancer, and no studies have tried to determine whether these epigenomic changes are associated with underlying DNA sequence changes or changes in the tumor immune microenvironment. Only by combining all of these multidimensional data will we be in the best position to address the biologic causes of racial disparities in prostate cancer. Here, we propose to determine the epigenomic landscape of primary prostate cancer arising in African Americans using large and highly annotated tumor cohorts. We will first profile African American prostate tumors (and some matched White controls) to determine whether there are apparent differences in the methylation marks between patients with differing racial ancestry. This will begin to answer the question of what other biologic differences may exist between prostate tumors arising in African American or White patients. We will then examine whether any of the epigenomic alterations in African American prostate cancer are associated with prostate cancer progression or metastasis, enabling us to create a biomarker of outcome specifically designed for African American patients. For these studies, we will use a discovery cohort of 200 African American and 200 White tumors with long-term follow-up, as well as DNA sequencing data, gene expression data, and tumor microenvironment data from Johns Hopkins University. Using a cohort of 300 tumors from Baylor College of Medicine, we will validate biomarkers discovered in the Johns Hopkins cohort. Finally, we will interrogate methylation in the largest prospective cohort of African American tumors ever collected, called the RESPOND study, which also has information about DNA sequencing, gene expression, and environmental and tumor microenvironmental characteristics. Taken together, these studies will help us complete the molecular picture of African American prostate cancer that was completed years ago in White patients with The Cancer Genome Atlas. Using this information, we will develop and validated novel markers of aggressive prostate cancer that may be clinically useful specifically in African Americans. In addition, with a more complete molecular picture of African American prostate cancer, we will for the first time be able to begin to design therapeutic strategies targeted to this population, eventually helping to close the gap between survival of African American
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910292
Entities
People
- Tamara L Lotan
Organizations
- Johns Hopkins University
- United States Army