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

摘要 非裔美国人(Aa)男性前列腺癌的发病率和死亡率在美国最高。 各州。我们最近发现，患有低风险前列腺癌的AA男性死亡风险增加了两倍 与其他种族的男性相比。虽然造成这种巨大差距的原因是多方面的，但我们 假设AA男性的低风险前列腺癌存在独特的基因组改变，导致更多 侵袭性前列腺癌。为此，我们对现有测序进行了初步的荟萃分析 研究发现了与血统相关的候选司机基因。然而，确定效果的能力 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，我们将使用完整发现与坡度相关的其他分子变化 来自欧洲背景的300名AA男性和200名男性前列腺癌病例的外显子组测序 来自波士顿医学中心和加州大学旧金山分校的存档标本集合。在目标2中，我们将描述 不同前列腺上皮细胞群转录和蛋白质组学状态的单细胞RNA- AA型和EA型有机化合物的SEQ和MS分析。在目标3中，我们将开发新的前列腺 使用条件重编程方法建立再生障碍性贫血患者的细胞模型。然后我们就会扰乱祖先--还有 利用CRISPR/Cas9基因组编辑与年级相关的驱动基因，确定是否有功能效应 这些基因中的一部分在不同的祖先背景中得到了增强。在这些研究结束后，我们将 扩展了我们对分子途径的理解，这些分子途径与不同的侵略性有关 祖传背景。我们还将从AA男性那里为 科学界调查前列腺癌的差异。这个项目将产生大量的知识 导致前列腺癌差异的机制最终可能导致改善前列腺癌的治疗 AA男性与前列腺癌患者的癌症健康差距缩小。

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.