Investigating the mechanisms of aggressive prostate cancer in African American Veterans

非洲裔美国人（AA）男性前列腺癌的发病率和死亡率最高， 美国的我们最近的研究表明，患有低风险前列腺癌的AA男性有两种 与其他种族的男性相比，死亡风险增加。虽然这种鲜明的原因 差异是多因素的，我们假设AA男性的前列腺癌具有独特的 基因组变异会导致更具侵袭性的前列腺癌。为此，我们 对现有的测序研究进行了初步的荟萃分析， 与祖先相关的基因然而，确定这些候选人的效果的能力 由于缺乏来自不同来源的生物细胞模型， 祖先的背景在目标1中，我们将发现与以下相关的其他分子改变： 使用全基因组测序的100名AA退伍军人前列腺癌病例的等级 在旧金山弗朗西斯科退伍军人事务医疗保健系统。在目标2中，我们将描述 不同前列腺上皮细胞群体的转录组状态，通过进行单细胞RNA- 源自AA和EA男性的类器官序列。在目标3中，我们将开发新的前列腺细胞模型 使用前列腺类器官的AA患者。然后我们将扰乱与祖先相关的驱动基因 并确定这些基因的功能效应是否在不同的祖先中增强， 背景在这些研究结束时，我们将扩大我们对 在不同的祖先背景中与攻击性相关的分子途径。 我们还将为科学界提供AA男性的前列腺细胞模型资源 研究前列腺癌的差异。该项目将产生大量的知识， 前列腺癌差异的基础机制，最终可能导致改善 治疗患有前列腺癌的AA男性和减少癌症健康差异。

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.