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

研究与前列腺癌的血统和侵袭性相关的驱动基因的机制

• 批准号: 10615833
• 负责人: Joshua D Campbell
• 金额: $ 19.74万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615833
• 关键词: Affect; African American; African American population; Age of Onset; American; Biochemical; Biological; Boston; CRISPR/Cas technology; Cancer Biology; Cell Line; Cell model; Cells; Clinical; Collection; Communities; Complement; DNA Sequence Alteration; Data; Diagnosis; Dimensions; Disease; Disparity; ETV3 gene; Epithelial Cells; European; Exhibits; Fractionation; Genes; Genetic; Genome; Gleason Grade for Prostate Cancer; Goals; Haplotypes; Incidence; Individual; Invaded; Knowledge; Life; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measures; Medical center; Meta-Analysis; Methods; Modeling; Molecular; Mutation; Oncogenes; Oncogenic; Organoids; Outcome; PTEN gene; Pathway interactions; Patients; Population; Prostate; Prostatectomy; Proteins; Proteomics; Radical Prostatectomy; Reporting; Resources; Socioeconomic Status; Sorting; Specimen; System; Testing; Tumor Suppressor Proteins; United States; Validation; Work; ZFHX3 gene; advanced disease; biological specimen archives; black men; cancer health disparity; candidate identification; cell growth; cofactor; cohort; early onset; epidemiologic data; exome sequencing; genome editing; health care availability; high risk; improved; innovative technologies; men; mortality; mortality disparity; mortality risk; novel; patient stratification; prostate cancer risk; racial disparity; racial population; response; single-cell RNA sequencing; therapy resistant; transcriptomics; tumor

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.

概括 在美国，非裔美国人 (AA) 男性的前列腺癌发病率和死亡率最高 国家。我们最近发现，患有低风险前列腺癌的 AA 男性的死亡风险增加两倍 与其他种族群体的男性相比。虽然造成这种明显差异的原因是多方面的，但我们 假设 AA 男性的低风险前列腺癌具有独特的基因组改变，从而导致更多 侵袭性前列腺癌。为此，我们对现有测序进行了初步荟萃分析 研究并发现了与血统相关的候选驱动基因。然而，确定效果的能力 由于缺乏不同来源的生物细胞模型，这些候选者在前列腺癌生物学方面的研究有限。 祖传背景。在目标 1 中，我们将使用整体发现与等级相关的其他分子改变 使用 300 名 AA 男性和 200 名欧洲背景男性的前列腺癌病例进行外显子组测序 波士顿医学中心和加州大学旧金山分校的存档标本集合。在目标 2 中，我们将描述 通过执行单细胞 RNA- 不同前列腺上皮细胞群的转录组和蛋白质组状态 对来自 AA 和 EA 人的类器官进行 seq 和质谱分析。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 AA 患者的细胞模型。然后我们就会扰乱祖先——并且 使用 CRISPR/Cas9 基因组编辑与等级相关的驱动基因并确定是否有功能影响 这些基因的一部分在不同的祖先背景中得到增强。在这些研究结束时，我们将 扩大了我们对与不同的攻击性相关的分子途径的理解 祖传背景。我们还将从 AA 男性中生成大量前列腺细胞模型资源，用于 科学界调查前列腺癌的差异。该项目将产生大量知识 前列腺癌差异背后的机制可能最终导致改善治疗 患有前列腺癌的 AA 男性和减少癌症健康差异。