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

总结 在美国，非洲裔美国人（AA）男性的前列腺癌发病率和死亡率最高。 States.我们最近发现患有低风险前列腺癌的AA男性死亡风险增加两倍 与其他种族的男性相比。虽然造成这种严重差异的原因是多方面的，但我们 假设AA男性中低风险前列腺癌具有独特的基因组改变， 侵袭性前列腺癌为此，我们对现有的测序进行了初步的荟萃分析， 研究并发现了与祖先相关的候选驱动基因。然而，确定影响的能力 由于缺乏来自不同来源的生物细胞模型，这些候选人对前列腺癌生物学的研究是有限的。 祖先的背景在目标1中，我们将发现与使用整体分级相关的其他分子改变。 来自300名AA男性和200名来自欧洲背景的男性的前列腺癌病例的外显子组测序， 波士顿医学中心和加州大学旧金山分校的存档标本集。在目标2中，我们将描述 转录组和蛋白质组状态的不同前列腺上皮细胞群体进行单细胞RNA- 来源于AA和EA的类器官的序列和质谱分析。在目标3中，我们将开发新的前列腺 使用条件性重编程方法从AA患者的细胞模型。然后我们会扰乱祖先-- 使用CRISPR/Cas9基因组编辑的梯度相关驱动基因，并确定功能效应是否 这些基因在不同的祖先背景中得到增强。在这些研究结束时，我们将 扩大了我们对分子途径的理解，这些分子途径与不同的 祖先的背景我们还将从AA男性中产生大量的前列腺细胞模型资源， 科学界调查前列腺癌的差异。该项目将产生大量的知识 前列腺癌差异的机制，最终可能导致改善治疗 AA男性前列腺癌和癌症健康差距的减少。

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.