Investigating the mechanisms of aggressive prostate cancer in African American Veterans

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African American (AA) men have the highest incidence and mortality rate from prostate cancer in the United States. We recently showed that AA men with low-risk prostate cancer have a two-fold increased risk of death compared to men of other racial groups. While the causes of this stark disparity are multifactorial, we hypothesize that prostate cancers in AA men harbor unique genomic alterations that give rise to more aggressive prostate cancer. Towards this end, we have performed an initial meta-analysis of existing sequencing studies and found candidate driver genes associated with ancestry. However, the ability to determine the effect of these candidates on prostate cancer biology is limited due to the lack of biological cell models from different ancestral backgrounds. In Aim 1, we will find additional molecular alterations associated with grade using whole genome sequencing of prostate cancer cases from 100 AA veteran men seen at the San Francisco Veterans Affairs Health Care System. In Aim 2, we will characterize the transcriptomic states of different prostate epithelial cell populations by performing single-cell RNA- seq of organoids derived from AA and EA men. In Aim 3, we will develop new prostate cell models from AA patients using prostate organoids. We will then perturb ancestry-associated driver genes and determine whether the functional effects of these genes are augmented in different ancestral backgrounds. At the conclusion of these studies we will have expanded our understanding of the molecular pathways that are associated with aggressiveness in different ancestral backgrounds. We will also generate a resource of prostate cell models from AA men for the scientific community to investigate prostate cancer disparities. This project will generate substantial knowledge of the mechanisms that underlie prostate cancer disparities that could ultimately lead to improved treatment of AA men with prostate cancer and the reduction of cancer health disparities.