Investigating the mechanisms of driver genes associated with ancestry and aggressiveness in prostate cancer

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Summary 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 low-risk prostate cancer 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 exome sequencing of prostate cancer cases from 300 AA men and 200 men from a European background using a collection of archived specimens from Boston Medical Center and UCSF. In Aim 2, we will characterize the transcriptomic and proteomic states of different prostate epithelial cell populations by performing single-cell RNA- seq and mass spectrometry of organoids derived from AA and EA men. In Aim 3, we will develop new prostate cell models from AA patients using a conditional reprogramming method. We will then perturb ancestry- and grade-associated driver genes using CRISPR/Cas9 genome editing 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 are associated with aggressiveness in different ancestral backgrounds. We will also generate a large 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.