Investigating the mechanisms of aggressive prostate cancer in African American Veterans

研究非裔美国退伍军人侵袭性前列腺癌的机制

• 批准号: 10370188
• 负责人: Franklin W Huang
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370188
• 关键词: Affect; African American; African American population; African ancestry; Age of Onset; American; Biological; Biopsy; CRISPR/Cas technology; Cancer Biology; Castrate sensitive prostate cancer; Cell Line; Cell model; Cells; Clinical; Communities; DNA Sequence Alteration; Data; Diagnosis; Diagnostic; Disease; Disparity; Dissection; ETV3 gene; Epithelial Cells; Epithelium; European; European ancestry; Exhibits; Frequencies; Future; Genes; Genome; Healthcare Systems; Heterogeneity; Hormones; Immune; Immune system; Immunologics; Immunotherapy; Incidence; Individual; Invaded; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Medical center; Meta-Analysis; Modeling; Molecular; Mutation; Oncogenes; Oncogenic; Open Reading Frames; Organoids; Outcome; PTEN gene; Pathway interactions; Patients; Population; Prostate; Prostatectomy; Prostatic Neoplasms; Radical Prostatectomy; Research; Resources; Role; San Francisco; Socioeconomic Status; Specimen; System; TMPRSS2 gene; Testing; Therapeutic; Therapeutic Trials; Tissues; United States; United States Department of Veterans Affairs; Veterans; Veterans Health Administration; ZFHX3 gene; advanced disease; black men; cancer diagnosis; cancer health disparity; cancer heterogeneity; cell growth; cell type; cohort; genetic information; genome sequencing; health care availability; high risk; improved; innovative technologies; insight; men; military veteran; mortality; mortality risk; novel; novel marker; participant enrollment; prostate cancer risk; racial population; recruit; single-cell RNA sequencing; socioeconomics; targeted treatment; therapy resistant; transcriptome; transcriptomics; tumor; tumor-immune system interactions; whole genome

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.

非裔美国人（AA）男性的发病率和死亡率最高 美国。我们最近表明，患有低风险前列腺癌的AA男性具有两倍 与其他种族群体的男性相比，死亡风险增加。而这个鲜明的原因 差异是多因素的，我们假设AA男子的前列腺癌藏有独特 基因组改变会导致更具侵略性的前列腺癌。为此，我们有 对现有测序研究进行了初步的荟萃分析，并发现了候选驱动程序 与祖先相关的基因。但是，确定这些候选人的效果的能力 由于缺乏不同的生物细胞模型，因此在前列腺癌的生物学上受到限制 祖先背景。在AIM 1中，我们会发现与 使用来自100名AA老兵的前列腺癌病例的整个基因组测序的等级 在旧金山退伍军人事务医疗系统。在AIM 2中，我们将表征 通过执行单细胞RNA-的不同前列腺上皮细胞种群的转录组态 源自AA和EA人的类器官。在AIM 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，我们将扰动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得到增强 背景。在这些研究结束时，我们将扩展我们对 与不同祖先背景的攻击性相关的分子途径。 我们还将为科学界从AA男子那里生成前列腺细胞模型的资源 研究前列腺癌的差异。该项目将对 前列腺癌差异的基础的机制最终可能会改善 治疗患有前列腺癌的AA男性和癌症健康差异的减少。