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在#年最高 美国。我们最近发现，患有低风险前列腺癌的AA男性有两倍于 与其他种族的男性相比，死亡风险更高。虽然造成这种严峻局面的原因 差异是多因素的，我们假设AA男性的前列腺癌是独特的 导致更具侵袭性的前列腺癌的基因组改变。为此，我们有 对现有测序研究进行了初步荟萃分析，并找到了候选驱动因素 与祖先相关的基因。然而，能够确定这些候选人的影响 由于缺乏不同来源的生物细胞模型，前列腺癌的生物学研究受到限制。 祖传背景。在目标1中，我们将发现与以下因素相关的其他分子变化 100例AA退伍军人前列腺癌全基因组测序分级 在旧金山退伍军人事务部医疗保健系统。在目标2中，我们将描述 单细胞RNA-RT-PCR技术检测不同前列腺上皮细胞群转录水平 从AA和EA人中提取的有机化合物的序列。在目标3中，我们将开发新的前列腺细胞模型 来自再生障碍性贫血患者使用的前列腺类器官。然后我们将扰乱与祖先相关的司机基因 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 在不同的祖先背景下与攻击性相关的分子途径。 我们还将为科学界提供来自AA男性的前列腺细胞模型资源 来调查前列腺癌的差异。这个项目将产生大量关于 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，减少癌症健康差距。

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.